chr6-7565476-A-G

Position:

• chr6-7565476-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_004415.4(DSP):​c.895A>G​(p.Ser299Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S299R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7565478-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.28647122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.895A>G	p.Ser299Gly	missense_variant	7/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.895A>G	p.Ser299Gly	missense_variant	7/24		NP_001305963.1
DSP	NM_001008844.3	c.895A>G	p.Ser299Gly	missense_variant	7/24		NP_001008844.1
DSP	NM_001406591.1	c.895A>G	p.Ser299Gly	missense_variant	7/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.895A>G	p.Ser299Gly	missense_variant	7/24	1	NM_004415.4	ENSP00000369129	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 28, 2016

The p.Ser299Gly variant in DSP has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. Another disease causing variant at the same position (Arg488C ys) has been reported in individuals with ARVC (Rampazzo 2002, Bauce 2005 and 20 01, Asimaki 2009, Rigato 2013), suggesting that changes at this position are not tolerated. In summary, the clinical significance of the p.Ser299Gly variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.26	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.24	B;.
Vest4		0.65
MutPred		0.52		Loss of stability (P = 0.0442);Loss of stability (P = 0.0442);
MVP		0.86
MPC		0.77
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.43
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657801; hg19: chr6-7565709;