11-110579499-G-T

Variant names:

• chr11-110579499-G-T
• rs775578516
• NM_001384657.1:c.3447C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001384657.1(ARHGAP20):​c.3447C>A​(p.Ser1149Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ARHGAP20 NM_001384657.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.667
• Publications: 1 publications found

Genes affected

ARHGAP20 (HGNC:18357): (Rho GTPase activating protein 20) The protein encoded by this gene is an activator of RHO-type GTPases, transducing a signal from RAP1 to RHO and impacting neurite outgrowth. [provided by RefSeq, Sep 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0280976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP20	NM_001384657.1	c.3447C>A	p.Ser1149Arg	missense_variant	Exon 15 of 15	ENST00000683387.1	NP_001371586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP20	ENST00000683387.1	c.3447C>A	p.Ser1149Arg	missense_variant	Exon 15 of 15		NM_001384657.1	ENSP00000507405.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000797 AC: 20 AN: 250956 AF XY: 0.0000811

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000196 AC: 3 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3447C>A (p.S1149R) alteration is located in exon 16 (coding exon 15) of the ARHGAP20 gene. This alteration results from a C to A substitution at nucleotide position 3447, causing the serine (S) at amino acid position 1149 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.027	T;T;.;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	T;T;T;.;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.028	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.
PhyloP100		0.67
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.97	N;N;N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.36	T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;B;.
Vest4		0.13
MutPred		0.21		Loss of phosphorylation at S1149 (P = 0.0103);.;.;.;.;.;
MVP		0.33
MPC		0.12
ClinPred		0.035	T
GERP RS		-0.85
Varity_R		0.079
gMVP		0.12
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs775578516; hg19: chr11-110450223;