rs3732413

Positions:

• chr3-119414336-G-A
• chr3-119414336-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020754.4(ARHGAP31):​c.2407G>A​(p.Gly803Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,614,002 control chromosomes in the GnomAD database, including 528,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53071 hom., cov: 32)
  • Exomes 𝑓: 0.81 (475063 hom.)
• Consequence: ARHGAP31 NM_020754.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.34

Genes affected

ARHGAP31 (HGNC:29216): (Rho GTPase activating protein 31) This gene encodes a GTPase-activating protein (GAP). A variety of cellular processes are regulated by Rho GTPases which cycle between an inactive form bound to GDP and an active form bound to GTP. This cycling between inactive and active forms is regulated by guanine nucleotide exchange factors and GAPs. The encoded protein is a GAP shown to regulate two GTPases involved in protein trafficking and cell growth. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.925418E-7).
• BP6: Variant 3-119414336-G-A is Benign according to our data. Variant chr3-119414336-G-A is described in ClinVar as [Benign]. Clinvar id is 342658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-119414336-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP31	NM_020754.4	c.2407G>A	p.Gly803Ser	missense_variant	12/12	ENST00000264245.9	NP_065805.2
ARHGAP31	XM_006713714.4	c.2347G>A	p.Gly783Ser	missense_variant	12/12		XP_006713777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP31	ENST00000264245.9	c.2407G>A	p.Gly803Ser	missense_variant	12/12	1	NM_020754.4	ENSP00000264245	P1

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126637 AN: 152044 Hom.: 53018 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.818

GnomAD3 exomes AF: 0.805 AC: 200682 AN: 249212 Hom.: 81227 AF XY: 0.807 AC XY: 109111 AN XY: 135210

Gnomad AFR exome AF: 0.918

Gnomad AMR exome AF: 0.729

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.869

Gnomad SAS exome AF: 0.861

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.790

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.805 AC: 1177034 AN: 1461840 Hom.: 475063 Cov.: 93 AF XY: 0.806 AC XY: 586300 AN XY: 727220

Gnomad4 AFR exome AF: 0.925

Gnomad4 AMR exome AF: 0.735

Gnomad4 ASJ exome AF: 0.714

Gnomad4 EAS exome AF: 0.889

Gnomad4 SAS exome AF: 0.861

Gnomad4 FIN exome AF: 0.837

Gnomad4 NFE exome AF: 0.798

Gnomad4 OTH exome AF: 0.806

GnomAD4 genome AF: 0.833 AC: 126748 AN: 152162 Hom.: 53071 Cov.: 32 AF XY: 0.835 AC XY: 62081 AN XY: 74390

Gnomad4 AFR AF: 0.914

Gnomad4 AMR AF: 0.783

Gnomad4 ASJ AF: 0.720

Gnomad4 EAS AF: 0.865

Gnomad4 SAS AF: 0.867

Gnomad4 FIN AF: 0.849

Gnomad4 NFE AF: 0.794

Gnomad4 OTH AF: 0.818

Alfa AF: 0.796 Hom.: 119023

Bravo AF: 0.829

TwinsUK AF: 0.806 AC: 2988

ALSPAC AF: 0.802 AC: 3092

ESP6500AA AF: 0.919 AC: 3463

ESP6500EA AF: 0.791 AC: 6498

ExAC AF: 0.808 AC: 97630

EpiCase AF: 0.785

EpiControl AF: 0.786

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 81% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2016	- -

Adams-Oliver syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0030
DANN	Benign	0.34
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.65	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.026
Sift	Benign	0.82	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.041
ClinPred		0.030	T
GERP RS		-10
Varity_R		0.013
gMVP		0.21

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: rs3732413; hg19: chr3-119133183; COSMIC: COSV51796888;