Genetic Variant ARHGAP12:p.Arg6Arg (chr10-31908840-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018287.7(ARHGAP12):c.16A>C(p.Arg6Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,591,894 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 133 hom. )

Consequence

ARHGAP12
NM_018287.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.47

Variant links:

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]

ARHGAP12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 10-31908840-T-G is Benign according to our data. Variant chr10-31908840-T-G is described in ClinVar as [Benign]. Clinvar id is 781939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00517 (787/152344) while in subpopulation SAS AF = 0.0344 (166/4820). AF 95% confidence interval is 0.0302. There are 6 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP12	NM_018287.7 link	c.16A>C	p.Arg6Arg	synonymous_variant	Exon 3 of 20	ENST00000344936.7	NP_060757.4	Q8IWW6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP12	ENST00000344936.7 link	c.16A>C	p.Arg6Arg	synonymous_variant	Exon 3 of 20	1	NM_018287.7	ENSP00000345808.2		Q8IWW6-1

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

788

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0346

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00601

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00897

AC:

2097

AN:

233700

AF XY:

0.0107

show subpopulations

Gnomad AFR exome

AF:

0.000998

Gnomad AMR exome

AF:

0.00458

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.000225

Gnomad NFE exome

AF:

0.00613

Gnomad OTH exome

AF:

0.00982

GnomAD4 exome

AF:

0.00763

AC:

10977

AN:

1439550

Hom.:

133

Cov.:

AF XY:

0.00865

AC XY:

6187

AN XY:

715266

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

33114

American (AMR)

AF:

0.00486

AC:

212

AN:

43578

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

334

AN:

25516

East Asian (EAS)

AF:

0.000101

AC:

AN:

39584

South Asian (SAS)

AF:

0.0371

AC:

3132

AN:

84402

European-Finnish (FIN)

AF:

0.000570

AC:

AN:

42106

Middle Eastern (MID)

AF:

0.0219

AC:

125

AN:

5700

European-Non Finnish (NFE)

AF:

0.00595

AC:

6581

AN:

1105690

Other (OTH)

AF:

0.00884

AC:

529

AN:

59860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

531

1062

1594

2125

2656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00517

AC:

787

AN:

152344

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41584

American (AMR)

AF:

0.00686

AC:

105

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.0344

AC:

166

AN:

4820

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00601

AC:

409

AN:

68024

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00721

Hom.:

Bravo

AF:

0.00500

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.6

(source)

DANN

Benign

0.82

PhyloP100

1.5

PromoterAI

0.035

Neutral

(source)

Mutation Taster

=100/0

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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chr10-31908840-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over