rs397515641

Positions:

• chr18-31329949-A-G
• chr18-31329949-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001942.4(DSG1):​c.430A>G​(p.Arg144Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DSG1 NM_001942.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

Genes affected

DSG1 (HGNC:3048): (desmoglein 1) This gene encodes a member of the desmoglein protein subfamily. Desmogleins, along with desmocollins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmoglein family members on chromosome 18. The encoded protein has been identified as a target of auto-antibodies in the autoimmune skin blistering disease pemphigus foliaceus. Disruption of this gene has also been associated with the skin diseases palmoplantar keratoderma and erythroderma. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG1	NM_001942.4	c.430A>G	p.Arg144Gly	missense_variant	5/15	ENST00000257192.5	NP_001933.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG1	ENST00000257192.5	c.430A>G	p.Arg144Gly	missense_variant	5/15	1	NM_001942.4	ENSP00000257192.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.59		Loss of stability (P = 0.0627);
MVP		0.80
MPC		0.47
ClinPred		1.0	D
GERP RS		0.47
Varity_R		0.66
gMVP		0.78

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: rs397515641; hg19: chr18-28909912;