18-31001724-A-G

Variant names:

• chr18-31001724-A-G
• NM_001941.5:c.2129T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001941.5(DSC3):​c.2129T>C​(p.Leu710Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DSC3 NM_001941.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC3	NM_001941.5	c.2129T>C	p.Leu710Ser	missense_variant	Exon 14 of 16	ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.2129T>C	p.Leu710Ser	missense_variant	Exon 14 of 17		NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.2129T>C	p.Leu710Ser	missense_variant	Exon 14 of 16	1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.2129T>C	p.Leu710Ser	missense_variant	Exon 14 of 17	5		ENSP00000392068.1
DSC3	ENST00000584980.1	c.251T>C	p.Leu84Ser	missense_variant	Exon 3 of 6	5		ENSP00000464283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453030 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.97	D;D
Vest4		0.78
MutPred		0.70		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.78
MPC		0.21
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28581690;