18-31001635-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001941.5(DSC3):c.2218C>T(p.Pro740Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,610,450 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: DSC3 NM_001941.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.52

Genes affected

DSC3 (HGNC:3037): (desmocollin 3) The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Mutations in this gene are a cause of hypotrichosis and recurrent skin vesicles disorder. The protein can act as an autoantigen in pemphigus diseases, and it is also considered to be a biomarker for some cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014158905).
• BP6: Variant 18-31001635-G-A is Benign according to our data. Variant chr18-31001635-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3033281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-31001635-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC3	NM_001941.5	c.2218C>T	p.Pro740Ser	missense_variant	14/16	ENST00000360428.9
DSC3	NM_024423.4	c.2218C>T	p.Pro740Ser	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC3	ENST00000360428.9	c.2218C>T	p.Pro740Ser	missense_variant	14/16	1	NM_001941.5	P1
DSC3	ENST00000434452.5	c.2218C>T	p.Pro740Ser	missense_variant	14/17	5
DSC3	ENST00000584980.1	c.343C>T	p.Pro115Ser	missense_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152034 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00548

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00236 AC: 593 AN: 250834 Hom.: 2 AF XY: 0.00250 AC XY: 339 AN XY: 135578

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00328 AC: 4776 AN: 1458298 Hom.: 8 Cov.: 30 AF XY: 0.00312 AC XY: 2264 AN XY: 725384

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000654

Gnomad4 FIN exome AF: 0.00541

Gnomad4 NFE exome AF: 0.00382

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152152 Hom.: 2 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74380

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00548

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00304 Hom.: 1

Bravo AF: 0.00204

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00250 AC: 303

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DSC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	28
Dann	Benign	0.95
DEOGEN2	Uncertain	0.48	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.56
MVP		0.80
MPC		0.27
ClinPred		0.078	T
GERP RS		4.5
Varity_R		0.68
gMVP		0.64

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: rs114935867; hg19: chr18-28581601; COSMIC: COSV64573915;