3-119294756-G-A

Variant names:

• chr3-119294756-G-A
• rs62265186
• NM_020754.4:c.-149G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020754.4(ARHGAP31):​c.-149G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 752,940 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (32 hom., cov: 31)
  • Exomes 𝑓: 0.018 (127 hom.)
• Consequence: ARHGAP31 NM_020754.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.372
• Publications: 4 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 (BayesDel_noAF=-0.79).
• BP6: Variant 3-119294756-G-A is Benign according to our data. Variant chr3-119294756-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1213601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (2175/152122) while in subpopulation NFE AF = 0.0203 (1379/67964). AF 95% confidence interval is 0.0194. There are 32 homozygotes in GnomAd4. There are 1146 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP31	NM_020754.4	c.-149G>A		5_prime_UTR_variant	Exon 1 of 12	ENST00000264245.9	NP_065805.2
ARHGAP31	XM_006713714.4	c.-149G>A		5_prime_UTR_variant	Exon 1 of 12		XP_006713777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP31	ENST00000264245.9	c.-149G>A		5_prime_UTR_variant	Exon 1 of 12	1	NM_020754.4	ENSP00000264245.4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2174 AN: 152004 Hom.: 32 Cov.: 31

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.0182 AC: 10931 AN: 600818 Hom.: 127 Cov.: 8 AF XY: 0.0186 AC XY: 5943 AN XY: 320376

African (AFR) AF: 0.00306 AC: 50 AN: 16360

American (AMR) AF: 0.00580 AC: 186 AN: 32070

Ashkenazi Jewish (ASJ) AF: 0.00918 AC: 171 AN: 18636

East Asian (EAS) AF: 0.00 AC: 0 AN: 32420

South Asian (SAS) AF: 0.0178 AC: 1097 AN: 61716

European-Finnish (FIN) AF: 0.0329 AC: 1187 AN: 36114

Middle Eastern (MID) AF: 0.0245 AC: 59 AN: 2404

European-Non Finnish (NFE) AF: 0.0208 AC: 7698 AN: 369394

Other (OTH) AF: 0.0152 AC: 483 AN: 31704

GnomAD4 genome AF: 0.0143 AC: 2175 AN: 152122 Hom.: 32 Cov.: 31 AF XY: 0.0154 AC XY: 1146 AN XY: 74366

African (AFR) AF: 0.00407 AC: 169 AN: 41542

American (AMR) AF: 0.00778 AC: 119 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4824

European-Finnish (FIN) AF: 0.0332 AC: 351 AN: 10584

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0203 AC: 1379 AN: 67964

Other (OTH) AF: 0.0123 AC: 26 AN: 2108

Alfa AF: 0.0201 Hom.: 4

Bravo AF: 0.0113

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 12, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		0.37
PromoterAI		-0.037	Neutral
Mutation Taster		=300/0	polymorphism

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: rs62265186; hg19: chr3-119013603;