rs751793

Positions:

• chr3-119383206-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020754.4(ARHGAP31):​c.662C>T​(p.Pro221Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,086 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: ARHGAP31 NM_020754.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.78

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052300096).
• BP6: Variant 3-119383206-C-T is Benign according to our data. Variant chr3-119383206-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 342634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-119383206-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP31	NM_020754.4	c.662C>T	p.Pro221Leu	missense_variant	6/12	ENST00000264245.9
ARHGAP31	XM_006713714.4	c.662C>T	p.Pro221Leu	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP31	ENST00000264245.9	c.662C>T	p.Pro221Leu	missense_variant	6/12	1	NM_020754.4	P1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00164 AC: 409 AN: 249574 Hom.: 1 AF XY: 0.00148 AC XY: 201 AN XY: 135404

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00189 AC: 2756 AN: 1461860 Hom.: 9 Cov.: 32 AF XY: 0.00182 AC XY: 1326 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74438

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00118

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00263 AC: 22

ExAC AF: 0.00186 AC: 225

EpiCase AF: 0.00180

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	ARHGAP31: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.063
Sift	Uncertain	0.016	D
Sift4G	Benign	0.098	T
Polyphen		0.20	B
Vest4		0.15
MVP		0.093
MPC		0.46
ClinPred		0.025	T
GERP RS		4.8
Varity_R		0.032
gMVP		0.42

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: rs751793; hg19: chr3-119102053;