6-138908735-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001286611.2(REPS1):c.2149G>A(p.Val717Ile) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,613,634 control chromosomes in the GnomAD database, including 19,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1763 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18087 hom.)
• Consequence: REPS1 NM_001286611.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.33

Genes affected

REPS1 (HGNC:15578): (RALBP1 associated Eps domain containing 1) This gene encodes a signaling adaptor protein with two EH domains that interacts with proteins that participate in signaling, endocytosis and cytoskeletal changes. The encoded protein has been found in association with intersectin 1 and Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 when intersectin 1 was isolated from clathrin-coated pits. The encoded protein has also been shown to interact with amphiphysin, a cytoplasmic protein at the surface of synaptic vesicles. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013096929).
• BP6: Variant 6-138908735-C-T is Benign according to our data. Variant chr6-138908735-C-T is described in ClinVar as [Benign]. Clinvar id is 1164210.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REPS1	NM_001286611.2	c.2149G>A	p.Val717Ile	missense_variant	18/20	ENST00000450536.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REPS1	ENST00000450536.7	c.2149G>A	p.Val717Ile	missense_variant	18/20	1	NM_001286611.2	P4

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22545 AN: 152048 Hom.: 1766 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0978

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.123 AC: 30834 AN: 251446 Hom.: 2397 AF XY: 0.120 AC XY: 16376 AN XY: 135900

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0662

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.0306

Gnomad SAS exome AF: 0.0530

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.151 AC: 221361 AN: 1461468 Hom.: 18087 Cov.: 32 AF XY: 0.148 AC XY: 107554 AN XY: 727046

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0694

Gnomad4 ASJ exome AF: 0.0693

Gnomad4 EAS exome AF: 0.0334

Gnomad4 SAS exome AF: 0.0511

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.148 AC: 22539 AN: 152166 Hom.: 1763 Cov.: 32 AF XY: 0.145 AC XY: 10785 AN XY: 74378

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0978

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.0531

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.125

Alfa AF: 0.151 Hom.: 3885

Bravo AF: 0.145

TwinsUK AF: 0.172 AC: 636

ALSPAC AF: 0.174 AC: 672

ESP6500AA AF: 0.176 AC: 777

ESP6500EA AF: 0.162 AC: 1395

ExAC AF: 0.127 AC: 15398

Asia WGS AF: 0.0590 AC: 204 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0087	T;.;T;.;.;T
Eigen	Benign	0.025
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T;T;T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.
MutationTaster	Benign	0.021	P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.26	N;N;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.0	B;.;.;P;B;B
Vest4		0.057
MPC		0.20
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.055
gMVP		0.048

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: rs1044418; hg19: chr6-139229872; COSMIC: COSV57810925; COSMIC: COSV57810925;