6-7565442-T-G

Variant names:

• chr6-7565442-T-G
• rs121912993
• NM_004415.4:c.861T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_004415.4(DSP):​c.861T>G​(p.Asn287Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.603

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 Likely_pathogenic. Variant got 9 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 6-7565442-T-G is Pathogenic according to our data. Variant chr6-7565442-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 16839.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.861T>G	p.Asn287Lys	missense_variant	Exon 7 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.861T>G	p.Asn287Lys	missense_variant	Exon 7 of 24		NP_001305963.1
DSP	NM_001008844.3	c.861T>G	p.Asn287Lys	missense_variant	Exon 7 of 24		NP_001008844.1
DSP	NM_001406591.1	c.861T>G	p.Asn287Lys	missense_variant	Exon 7 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.861T>G	p.Asn287Lys	missense_variant	Exon 7 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;T
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.80		Gain of methylation at N287 (P = 0.0172);Gain of methylation at N287 (P = 0.0172);
MVP		0.91
MPC		0.88
ClinPred		1.0	D
GERP RS		-5.9
Varity_R		0.91
gMVP		0.79

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: rs121912993; hg19: chr6-7565675;