6-7576437-G-C

Variant summary

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

The NM_004415.4(DSP):c.2774G>C(p.Arg925Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R925Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76

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/exons	MANE	UniProt
DSP	NM_004415.4	c.2774G>C	p.Arg925Pro	missense_variant	19/24	ENST00000379802.8
DSP	NM_001319034.2	c.2774G>C	p.Arg925Pro	missense_variant	19/24
DSP	NM_001008844.3	c.2774G>C	p.Arg925Pro	missense_variant	19/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.2774G>C	p.Arg925Pro	missense_variant	19/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.2774G>C	p.Arg925Pro	missense_variant	19/24	1		A2
DSP	ENST00000710359.1	c.2774G>C	p.Arg925Pro	missense_variant	19/24			A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.87	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.076	T;D
Sift4G	Uncertain	0.038	D;T
Polyphen		0.80	P;.
Vest4		0.64
MutPred		0.45		Loss of MoRF binding (P = 0.0599);Loss of MoRF binding (P = 0.0599);
MVP		0.52
MPC		0.67
ClinPred		0.83	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.68

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: rs139799237; hg19: chr6-7576670;