15-32624213-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014783.6(ARHGAP11A):c.338C>T(p.Pro113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,134 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGAP11A NM_014783.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.546

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04419583).
• BP6: Variant 15-32624213-C-T is Benign according to our data. Variant chr15-32624213-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3128491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP11A	NM_014783.6	c.338C>T	p.Pro113Leu	missense_variant	4/12	ENST00000361627.8
ARHGAP11A-SCG5	NM_001368319.1	c.338C>T	p.Pro113Leu	missense_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP11A	ENST00000361627.8	c.338C>T	p.Pro113Leu	missense_variant	4/12	1	NM_014783.6	P1
	ENST00000647892.1	n.2121G>A		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150836 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247574 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461134 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000133 AC: 2 AN: 150836 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73510

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	12
Dann	Benign	0.43
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.84	T;D;.
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.59	N;N;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.40	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.22
MutPred		0.58		Loss of disorder (P = 0.0526);Loss of disorder (P = 0.0526);Loss of disorder (P = 0.0526);
MVP		0.40
MPC		1.2
ClinPred		0.029	T
GERP RS		-1.2
Varity_R		0.076
gMVP		0.14

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: rs1340082884; hg19: chr15-32916414;