20-38634654-C-T

Variant names:

• chr20-38634654-C-T
• rs1014530768
• NM_001164431.3:c.818C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001164431.3(ARHGAP40):​c.818C>T​(p.Thr273Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,305,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ARHGAP40 NM_001164431.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77
• Publications: 0 publications found

Genes affected

ARHGAP40 (HGNC:16226): (Rho GTPase activating protein 40) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of actin filament polymerization and regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3041396).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164431.3. 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
	ARHGAP40	NM_001164431.3	MANE Select	c.818C>T	p.Thr273Met	missense	Exon 6 of 15	NP_001157903.2	Q5TG30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP40	ENST00000373345.9	TSL:5 MANE Select	c.818C>T	p.Thr273Met	missense	Exon 6 of 15	ENSP00000362442.5	Q5TG30
	ARHGAP40	ENST00000906550.1		c.593C>T	p.Thr198Met	missense	Exon 4 of 13	ENSP00000576609.1
	ARHGAP40	ENST00000243967.8	TSL:5	c.479C>T	p.Thr160Met	missense	Exon 4 of 14	ENSP00000243967.4	H7BXE0

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000639 AC: 1 AN: 156560 AF XY: 0.0000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

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: 0.0000121 AC: 14 AN: 1153100 Hom.: 0 Cov.: 31 AF XY: 0.0000106 AC XY: 6 AN XY: 565414

African (AFR) AF: 0.00 AC: 0 AN: 24418

American (AMR) AF: 0.0000354 AC: 1 AN: 28270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15940

East Asian (EAS) AF: 0.00 AC: 0 AN: 12844

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28460

Middle Eastern (MID) AF: 0.000227 AC: 1 AN: 4404

European-Non Finnish (NFE) AF: 0.0000119 AC: 11 AN: 920930

Other (OTH) AF: 0.00 AC: 0 AN: 41634

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

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

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000189

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	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.8
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.065
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.26
MutPred		0.39		Gain of MoRF binding (P = 0.0776)
MVP		0.17
ClinPred		0.94	D
GERP RS		2.0
Varity_R		0.062
gMVP		0.68
Mutation Taster		=91/9	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: rs1014530768; hg19: chr20-37263297;