rs377507763

Variant names:

• chr6-7559324-G-A
• rs377507763
• NM_004415.4:c.521G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7559324-G-A
• chr6-7559324-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004415.4(DSP):​c.521G>A​(p.Cys174Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C174C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.521G>A	p.Cys174Tyr	missense_variant	Exon 4 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.521G>A	p.Cys174Tyr	missense_variant	Exon 4 of 24		NP_001305963.1
DSP	NM_001008844.3	c.521G>A	p.Cys174Tyr	missense_variant	Exon 4 of 24		NP_001008844.1
DSP	NM_001406591.1	c.521G>A	p.Cys174Tyr	missense_variant	Exon 4 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.521G>A	p.Cys174Tyr	missense_variant	Exon 4 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251302 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.028	D;T
Sift4G	Benign	0.070	T;T
Polyphen		0.88	P;.
Vest4		0.63
MutPred		0.25		Gain of phosphorylation at C174 (P = 0.0431);Gain of phosphorylation at C174 (P = 0.0431);
MVP		0.65
MPC		0.73
ClinPred		0.34	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.42

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: rs377507763; hg19: chr6-7559557; COSMIC: COSV65794441;