chr10-31812769-A-G

Position:

• chr10-31812769-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018287.7(ARHGAP12):​c.1889T>C​(p.Leu630Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ARHGAP12 NM_018287.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

Genes affected

ARHGAP12 (HGNC:16348): (Rho GTPase activating protein 12) This gene encodes a member of a large family of proteins that activate Rho-type guanosine triphosphate (GTP) metabolizing enzymes. The encoded protein may be involved in suppressing tumor formation by regulating cell invasion and adhesion. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP12	NM_018287.7	c.1889T>C	p.Leu630Ser	missense_variant	15/20	ENST00000344936.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP12	ENST00000344936.7	c.1889T>C	p.Leu630Ser	missense_variant	15/20	1	NM_018287.7

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74238

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.1889T>C (p.L630S) alteration is located in exon 15 (coding exon 13) of the ARHGAP12 gene. This alteration results from a T to C substitution at nucleotide position 1889, causing the leucine (L) at amino acid position 630 to be replaced by a serine (S). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.6	.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.3	.;D;D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.88
MutPred		0.38		.;.;.;.;Loss of stability (P = 0.008);
MVP		0.49
MPC		0.87
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1835068118; hg19: chr10-32101697;