Genetic Variant ARHGAP31:c.100+148dupT (chr3-119295140-C-CT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020754.4(ARHGAP31):c.100+148dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 594,554 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 17)

Exomes 𝑓: 0.030 ( 0 hom. )

Consequence

ARHGAP31
NM_020754.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0770

Publications

0 publications found

Variant links:

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

ARHGAP31 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP31	NM_020754.4 link	c.100+148dupT		intron_variant	Intron 1 of 11	ENST00000264245.9	NP_065805.2	Q2M1Z3A0A8S0MHV1
ARHGAP31	XM_006713714.4 link	c.100+148dupT		intron_variant	Intron 1 of 11		XP_006713777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP31	ENST00000264245.9 link	c.100+136_100+137insT		intron_variant	Intron 1 of 11	1	NM_020754.4	ENSP00000264245.4		Q2M1Z3

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

378

AN:

139806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000801

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00148

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000214

Gnomad SAS

AF:

0.000923

Gnomad FIN

AF:

0.00219

Gnomad MID

AF:

0.00331

Gnomad NFE

AF:

0.00459

Gnomad OTH

AF:

0.00471

GnomAD4 exome

AF:

0.0297

AC:

13497

AN:

454678

Hom.:

AF XY:

0.0296

AC XY:

7187

AN XY:

243000

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0101

AC:

117

AN:

11576

American (AMR)

AF:

0.0335

AC:

614

AN:

18352

Ashkenazi Jewish (ASJ)

AF:

0.0316

AC:

437

AN:

13832

East Asian (EAS)

AF:

0.0356

AC:

825

AN:

23190

South Asian (SAS)

AF:

0.0157

AC:

686

AN:

43706

European-Finnish (FIN)

AF:

0.0277

AC:

765

AN:

27606

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

2768

European-Non Finnish (NFE)

AF:

0.0323

AC:

9348

AN:

289756

Other (OTH)

AF:

0.0281

AC:

671

AN:

23892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.273

Heterozygous variant carriers

1602

3204

4807

6409

8011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00270

AC:

378

AN:

139876

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

170

AN XY:

67586

show subpopulations

African (AFR)

AF:

0.000799

AC:

AN:

38788

American (AMR)

AF:

0.00155

AC:

AN:

13510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3244

East Asian (EAS)

AF:

0.000214

AC:

AN:

4668

South Asian (SAS)

AF:

0.000926

AC:

AN:

4318

European-Finnish (FIN)

AF:

0.00219

AC:

AN:

8232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00459

AC:

294

AN:

64046

Other (OTH)

AF:

0.00467

AC:

AN:

1928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000531

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.077

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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3-119295140-CTTTTTTTTT-CTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over