NM_020754.4:c.2407G>A

Variant names:

• chr3-119414336-G-A
• rs3732413
• NM_020754.4:c.2407G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 34 publications found

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]

ARHGAP31 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 342658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020754.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP31	NM_020754.4	MANE Select	c.2407G>A	p.Gly803Ser	missense	Exon 12 of 12	NP_065805.2	A0A8S0MHV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP31	ENST00000264245.9	TSL:1 MANE Select	c.2407G>A	p.Gly803Ser	missense	Exon 12 of 12	ENSP00000264245.4	Q2M1Z3
	ARHGAP31	ENST00000861944.1		c.2347G>A	p.Gly783Ser	missense	Exon 12 of 12	ENSP00000532003.1

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

GnomAD2 exomes AF: 0.805 AC: 200682 AN: 249212 AF XY: 0.807

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 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

African (AFR) AF: 0.925 AC: 30984 AN: 33480

American (AMR) AF: 0.735 AC: 32873 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 18664 AN: 26134

East Asian (EAS) AF: 0.889 AC: 35304 AN: 39700

South Asian (SAS) AF: 0.861 AC: 74239 AN: 86258

European-Finnish (FIN) AF: 0.837 AC: 44735 AN: 53416

Middle Eastern (MID) AF: 0.786 AC: 4536 AN: 5768

European-Non Finnish (NFE) AF: 0.798 AC: 887001 AN: 1111964

Other (OTH) AF: 0.806 AC: 48698 AN: 60396

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

African (AFR) AF: 0.914 AC: 37926 AN: 41514

American (AMR) AF: 0.783 AC: 11978 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2496 AN: 3466

East Asian (EAS) AF: 0.865 AC: 4462 AN: 5158

South Asian (SAS) AF: 0.867 AC: 4175 AN: 4818

European-Finnish (FIN) AF: 0.849 AC: 8998 AN: 10602

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 54007 AN: 67996

Other (OTH) AF: 0.818 AC: 1724 AN: 2108

Alfa AF: 0.799 Hom.: 169281

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Adams-Oliver syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-2.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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