17-76007414-C-T

Variant names:

• chr17-76007414-C-T
• rs146869766
• NM_001988.4:c.5791G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001988.4(EVPL):​c.5791G>A​(p.Val1931Met) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,603,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: EVPL NM_001988.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

Genes affected

EVPL (HGNC:3503): (envoplakin) This gene encodes a member of the plakin family of proteins that forms a component of desmosomes and the epidermal cornified envelope. This gene is located in the tylosis oesophageal cancer locus on chromosome 17q25, and its deletion is associated with both familial and sporadic forms of oesophageal squamous cell carcinoma. Patients suffering from the autoimmune mucocutaneous disorder, paraneoplastic pemphigus, develop antibodies against the encoded protein. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04193011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVPL	NM_001988.4	c.5791G>A	p.Val1931Met	missense_variant	Exon 22 of 22	ENST00000301607.8	NP_001979.2
EVPL	NM_001320747.2	c.5857G>A	p.Val1953Met	missense_variant	Exon 22 of 22		NP_001307676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVPL	ENST00000301607.8	c.5791G>A	p.Val1931Met	missense_variant	Exon 22 of 22	1	NM_001988.4	ENSP00000301607.3
EVPL	ENST00000586740.1	c.5857G>A	p.Val1953Met	missense_variant	Exon 22 of 22	1		ENSP00000465630.1
EVPL	ENST00000589231.1	c.28G>A	p.Val10Met	missense_variant	Exon 1 of 2	3		ENSP00000467717.1
EVPL	ENST00000587569.5	n.6260G>A		non_coding_transcript_exon_variant	Exon 20 of 20	2

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000141 AC: 35 AN: 247836 Hom.: 0 AF XY: 0.000127 AC XY: 17 AN XY: 133936

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000723 AC: 105 AN: 1451642 Hom.: 0 Cov.: 31 AF XY: 0.0000749 AC XY: 54 AN XY: 720540

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000335

Gnomad4 OTH exome AF: 0.0000834

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74466

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000502

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5791G>A (p.V1931M) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a G to A substitution at nucleotide position 5791, causing the valine (V) at amino acid position 1931 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T;.
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.15
Sift	Uncertain	0.013	.;D;.
Sift4G	Uncertain	0.047	D;D;D
Polyphen		0.52	.;P;.
Vest4		0.15, 0.20
MVP		0.67
MPC		0.25
ClinPred		0.040	T
GERP RS		3.5
Varity_R		0.24
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146869766; hg19: chr17-74003495;