rs145484357

Variant names:

• chr15-32629621-C-T
• rs145484357
• NM_014783.6:c.964C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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. 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
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16806322).

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.964C>T	p.Leu322Phe	missense	Exon 8 of 12	NP_055598.1	Q6P4F7-1
	ARHGAP11A	NM_001286479.3		c.397C>T	p.Leu133Phe	missense	Exon 8 of 12	NP_001273408.1	Q6P4F7-3
	ARHGAP11A	NM_001286480.3		c.397C>T	p.Leu133Phe	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.964C>T	p.Leu322Phe	missense	Exon 8 of 12	ENSP00000355090.3	Q6P4F7-1
	ARHGAP11A-SCG5	ENST00000692248.1		c.964C>T	p.Leu322Phe	missense	Exon 8 of 14	ENSP00000510771.1	A0A8I5KWH8
	ARHGAP11A	ENST00000567348.5	TSL:1	c.964C>T	p.Leu322Phe	missense	Exon 8 of 11	ENSP00000454575.1	Q6P4F7-2

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

GnomAD2 exomes AF: 0.0000604 AC: 15 AN: 248276 AF XY: 0.0000745

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 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

African (AFR) AF: 0.0000600 AC: 2 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85330

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000215 AC: 239 AN: 1110842

Other (OTH) AF: 0.000133 AC: 8 AN: 60274

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

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

ClinVar submissions as Germline

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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.098
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.018	D
Sift4G	Benign	0.14	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
Mutation Taster		=83/17	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: rs145484357; hg19: chr15-32921822; COSMIC: COSV100853232; COSMIC: COSV100853232;