15-32629640-G-A

Variant names:

• chr15-32629640-G-A
• rs367930258
• NM_014783.6:c.983G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014783.6(ARHGAP11A):​c.983G>A​(p.Arg328His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R328C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ARHGAP11A NM_014783.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.04
• Publications: 2 publications found

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:56310): (ARHGAP11A-SCG5 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ARHGAP11A (Rho GTPase activating protein 11A) and SCG5 (secretogranin V) genes on chromosome 15q13.3. The readthrough transcript encodes a fusion protein that shares sequence identity with both the ARHGAP11A and SCG5 gene products. [provided by RefSeq, Feb 2019]

ENSG00000285948 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014783.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP11A	NM_014783.6	MANE Select	c.983G>A	p.Arg328His	missense	Exon 8 of 12	NP_055598.1	Q6P4F7-1
	ARHGAP11A	NM_001286479.3		c.416G>A	p.Arg139His	missense	Exon 8 of 12	NP_001273408.1	Q6P4F7-3
	ARHGAP11A	NM_001286480.3		c.416G>A	p.Arg139His	missense	Exon 9 of 13	NP_001273409.1	Q6P4F7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP11A	ENST00000361627.8	TSL:1 MANE Select	c.983G>A	p.Arg328His	missense	Exon 8 of 12	ENSP00000355090.3	Q6P4F7-1
	ARHGAP11A-SCG5	ENST00000692248.1		c.983G>A	p.Arg328His	missense	Exon 8 of 14	ENSP00000510771.1	A0A8I5KWH8
	ARHGAP11A	ENST00000567348.5	TSL:1	c.983G>A	p.Arg328His	missense	Exon 8 of 11	ENSP00000454575.1	Q6P4F7-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 11 AN: 250436 AF XY: 0.0000369

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461032 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726786

African (AFR) AF: 0.000269 AC: 9 AN: 33450

American (AMR) AF: 0.000202 AC: 9 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111638

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 27 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

African (AFR) AF: 0.000169 AC: 7 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000549 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.95
MPC		0.27
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.53
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs367930258; hg19: chr15-32921841; COSMIC: COSV64381554; COSMIC: COSV64381554;