6-7542072-T-G

Variant names:

• chr6-7542072-T-G
• rs397516918
• NM_004415.4:c.157T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004415.4(DSP):​c.157T>G​(p.Ser53Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,563,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S53P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.04
• 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-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057244897).
• BP6: Variant 6-7542072-T-G is Benign according to our data. Variant chr6-7542072-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44864.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00021 (32/152238) while in subpopulation AMR AF = 0.00209 (32/15304). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.157T>G	p.Ser53Ala	missense	Exon 1 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.157T>G	p.Ser53Ala	missense	Exon 1 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.157T>G	p.Ser53Ala	missense	Exon 1 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.157T>G	p.Ser53Ala	missense	Exon 1 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.157T>G	p.Ser53Ala	missense	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.157T>G	p.Ser53Ala	missense	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.00117 AC: 192 AN: 163682 AF XY: 0.000913

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00724

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000162 AC: 228 AN: 1411744 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 96 AN XY: 697600

African (AFR) AF: 0.00 AC: 0 AN: 32166

American (AMR) AF: 0.00602 AC: 227 AN: 37716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25300

East Asian (EAS) AF: 0.00 AC: 0 AN: 36714

South Asian (SAS) AF: 0.00 AC: 0 AN: 80288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086480

Other (OTH) AF: 0.0000171 AC: 1 AN: 58526

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00209 AC: 32 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000570

ExAC AF: 0.000672 AC: 78

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DSP-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.11
Sift	Benign	0.080	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.52
MPC		0.18
ClinPred		0.087	T
GERP RS		2.6
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.36
Mutation Taster		=91/9	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: rs397516918; hg19: chr6-7542305;