NM_004415.4:c.5779C>G

Variant names:

• chr6-7583041-C-G
• rs794728104
• NM_004415.4:c.5779C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004415.4(DSP):​c.5779C>G​(p.Gln1927Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 4.98
• Publications: 1 publications found

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DSP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06748441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.5779C>G	p.Gln1927Glu	missense_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4450C>G	p.Gln1484Glu	missense_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.3982C>G	p.Gln1328Glu	missense_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5779C>G	p.Gln1927Glu	missense_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250848 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Gln1927Glu va riant in DSP has not been previously reported in individuals with cardiomyopathy or in large population studies. Glutamine (Gln) at position 1927 is conserved i n mammals but not in evolutionarily distant species and >10 avian species carry a glutamic acid (Glu), raising the possibility that this change may be tolerated . Additional computational prediction tools support that the p.Gln1927Glu varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. In summary, while the clinical significance of the p.G ln1927Glu variant is uncertain, the presence of the variant amino acid in multip le other species suggests that it is more likely to be benign. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with glutamic acid at codon 1927 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1927 of the DSP protein (p.Gln1927Glu). This variant is present in population databases (rs794728104, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 199844). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with glutamic acid at codon 1927 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Aug 01, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the DSP gene. The Q1927E variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been classifiedin ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000271735.1; Landrum etal., 2016). In addition, the Q1927E variant has previously been identified in one other unrelated individual referred forcardiomyopathy genetic testing at GeneDx who also harbored a pathogenic variant in the RAF1 gene. This variantwas not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The Q1927E variantis a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differin some properties. This substitution occurs at a position that is conserved in mammals. However, Glutamic acid isthe wild type amino acid at this position in multiple species. Furthermore, in silico analysis is inconsistent in itspredictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Cardiovascular phenotype Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1927E variant (also known as c.5779C>G), located in coding exon 24 of the DSP gene, results from a C to G substitution at nucleotide position 5779. The glutamine at codon 1927 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.83	N;.
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.099
Sift	Benign	0.61	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.093
MVP		0.31
MPC		0.24
ClinPred		0.29	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.27
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728104; hg19: chr6-7583274;