6-7570492-A-T

Variant names:

• chr6-7570492-A-T
• rs201960323
• NM_004415.4:c.1630A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004415.4(DSP):​c.1630A>T​(p.Met544Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38936174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1630A>T	p.Met544Leu	missense_variant	Exon 13 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1630A>T	p.Met544Leu	missense_variant	Exon 13 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1630A>T	p.Met544Leu	missense_variant	Exon 13 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1630A>T	p.Met544Leu	missense_variant	Exon 13 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1630A>T	p.Met544Leu	missense_variant	Exon 13 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1630A>T	p.Met544Leu	missense_variant	Exon 13 of 24			ENSP00000518230.1
DSP	ENST00000684395.1	n.14A>T		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D;T
Sift4G	Benign	0.40	T;T
Polyphen		0.14	B;.
Vest4		0.60
MutPred		0.45		Gain of ubiquitination at K545 (P = 0.1375);Gain of ubiquitination at K545 (P = 0.1375);
MVP		0.79
MPC		0.65
ClinPred		0.84	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.66

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: rs201960323; hg19: chr6-7570725;