Genetic Variant ARHGAP11A:p.Ser452Phe (chr15-32635787-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014783.6(ARHGAP11A):c.1355C>T(p.Ser452Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,445,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S452C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ARHGAP11A
NM_014783.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

Publications

2 publications found

Variant links:

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 links:

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]

ARHGAP11A-SCG5 links:

ENSG00000285948 (HGNC:):

ENSG00000285948 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2098116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP11A	NM_014783.6 link	c.1355C>T	p.Ser452Phe	missense_variant	Exon 11 of 12	ENST00000361627.8	NP_055598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP11A	ENST00000361627.8 link	c.1355C>T	p.Ser452Phe	missense_variant	Exon 11 of 12	1	NM_014783.6	ENSP00000355090.3
ARHGAP11A-SCG5	ENST00000692248.1 link	c.1235+2679C>T		intron_variant	Intron 9 of 13			ENSP00000510771.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000835

AC:

AN:

239390

AF XY:

0.00000771

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000637

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:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1445400

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32672

American (AMR)

AF:

0.0000481

AC:

AN:

41608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25704

East Asian (EAS)

AF:

0.00

AC:

AN:

38882

South Asian (SAS)

AF:

0.00

AC:

AN:

83006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105302

Other (OTH)

AF:

0.00

AC:

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;T;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

LIST_S2

Benign

0.0

.;T;T;.;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;M;M;.;.

PhyloP100

1.3

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.7

D;D;D;D;D

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Vest4

0.27

ClinPred

0.90

GERP RS

5.2

Varity_R

0.31

gMVP

0.19

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over