chr6-7581514-G-A

Position:

• chr6-7581514-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The ENST00000379802.8(DSP):​c.5324G>A​(p.Arg1775Lys) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1775I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP ENST00000379802.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7581514-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.070530295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.5324G>A	p.Arg1775Lys	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.3583-1128G>A		intron_variant			NP_001008844.1
DSP	NM_001319034.2	c.4051-1128G>A		intron_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5324G>A	p.Arg1775Lys	missense_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3583-1128G>A		intron_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4051-1128G>A		intron_variant				ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	0.78	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.082
Sift	Benign	0.29	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.092
MutPred		0.27		Gain of ubiquitination at R1775 (P = 0.0025);
MVP		0.44
MPC		0.22
ClinPred		0.58	D
GERP RS		5.2
Varity_R		0.065
gMVP		0.15

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: rs34738426; hg19: chr6-7581747;