chr15-32629642-A-G

Variant names:

• chr15-32629642-A-G
• rs74011135
• NM_014783.6:c.985A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.985A>G	p.Thr329Ala	missense	Exon 8 of 12	NP_055598.1	Q6P4F7-1
	ARHGAP11A	NM_001286479.3		c.418A>G	p.Thr140Ala	missense	Exon 8 of 12	NP_001273408.1	Q6P4F7-3
	ARHGAP11A	NM_001286480.3		c.418A>G	p.Thr140Ala	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.985A>G	p.Thr329Ala	missense	Exon 8 of 12	ENSP00000355090.3	Q6P4F7-1
	ARHGAP11A-SCG5	ENST00000692248.1		c.985A>G	p.Thr329Ala	missense	Exon 8 of 14	ENSP00000510771.1	A0A8I5KWH8
	ARHGAP11A	ENST00000567348.5	TSL:1	c.985A>G	p.Thr329Ala	missense	Exon 8 of 11	ENSP00000454575.1	Q6P4F7-2

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

GnomAD2 exomes AF: 0.00168 AC: 420 AN: 250600 AF XY: 0.00114

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 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

African (AFR) AF: 0.0227 AC: 760 AN: 33460

American (AMR) AF: 0.00101 AC: 45 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111732

Other (OTH) AF: 0.00134 AC: 81 AN: 60362

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

African (AFR) AF: 0.0210 AC: 872 AN: 41578

American (AMR) AF: 0.00203 AC: 31 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00245 Hom.: 7

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.0	N
PhyloP100		8.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs74011135; hg19: chr15-32921843;