15-32629621-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014783.6(ARHGAP11A):c.964C>T(p.Leu322Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,610,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ARHGAP11A NM_014783.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16806322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP11A	NM_014783.6	c.964C>T	p.Leu322Phe	missense_variant	8/12	ENST00000361627.8
ARHGAP11A-SCG5	NM_001368319.1	c.964C>T	p.Leu322Phe	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP11A	ENST00000361627.8	c.964C>T	p.Leu322Phe	missense_variant	8/12	1	NM_014783.6	P1
	ENST00000647892.1	n.575-2705G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152156 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000604 AC: 15 AN: 248276 Hom.: 0 AF XY: 0.0000745 AC XY: 10 AN XY: 134146

Gnomad AFR exome AF: 0.0000618

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: 0.000115

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1458704 Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 128 AN XY: 725514

Gnomad4 AFR exome AF: 0.0000600

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: 0.0000187

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152156 Hom.: 0 Cov.: 27 AF XY: 0.0000673 AC XY: 5 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000219

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.964C>T (p.L322F) alteration is located in exon 8 (coding exon 8) of the ARHGAP11A gene. This alteration results from a C to T substitution at nucleotide position 964, causing the leucine (L) at amino acid position 322 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.098
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.74	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;N;N;N;N
Sift	Uncertain	0.018	D;D;T;D;D
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.84	.;P;.;.;.
Vest4		0.22
MVP		0.93
MPC		0.15
ClinPred		0.31	T
GERP RS		1.2
Varity_R		0.064
gMVP		0.17

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: rs145484357; hg19: chr15-32921822; COSMIC: COSV100853232; COSMIC: COSV100853232;