15-32629642-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014783.6(ARHGAP11A):c.985A>G(p.Thr329Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,562 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (11 hom., cov: 27)
  • Exomes 𝑓: 0.00062 (7 hom.)
• Consequence: ARHGAP11A NM_014783.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.42

Genes affected

ARHGAP11A (HGNC:15783): (Rho GTPase activating protein 11A) This gene encodes a member of the Rho GTPase activating protein family. In response to DNA damage, the encoded protein interacts with the p53 tumor suppressor protein and stimulates its tetramerization, which results in cell-cycle arrest and apoptosis. A chromosomal deletion that includes this gene is one cause of Prader-Willi syndrome, and an intronic variant of this gene may be associated with sleep duration in children. This gene is highly expressed in colon cancers and in a human basal-like breast cancer cell line. This gene also produces a ARHGAP11A-SCG5 readthrough transcript and ARHGAP11A-SCG5 protein. [provided by RefSeq, Feb 2019]

ARHGAP11A-SCG5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007574767).
• BP6: Variant 15-32629642-A-G is Benign according to our data. Variant chr15-32629642-A-G is described in ClinVar as [Benign]. Clinvar id is 785480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00603 (919/152336) while in subpopulation AFR AF= 0.021 (872/41578). AF 95% confidence interval is 0.0198. There are 11 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP11A	NM_014783.6	c.985A>G	p.Thr329Ala	missense_variant	8/12	ENST00000361627.8
ARHGAP11A-SCG5	NM_001368319.1	c.985A>G	p.Thr329Ala	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP11A	ENST00000361627.8	c.985A>G	p.Thr329Ala	missense_variant	8/12	1	NM_014783.6	P1
	ENST00000647892.1	n.575-2726T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152218 Hom.: 11 Cov.: 27

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00168 AC: 420 AN: 250600 Hom.: 1 AF XY: 0.00114 AC XY: 155 AN XY: 135458

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000615 AC: 899 AN: 1461226 Hom.: 7 Cov.: 31 AF XY: 0.000542 AC XY: 394 AN XY: 726908

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00603 AC: 919 AN: 152336 Hom.: 11 Cov.: 27 AF XY: 0.00569 AC XY: 424 AN XY: 74484

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.00703

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00208 AC: 253

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	-0.053
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0076	T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.10	N;N;N;N;N
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.0	.;B;.;.;.
Vest4		0.32
MVP		0.85
MPC		0.032
ClinPred		0.056	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs74011135; hg19: chr15-32921843;