11-100687818-T-A

Variant names:

• chr11-100687818-T-A
• rs1012498540
• NM_152432.4:c.140T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001367945.1(ARHGAP42):​c.-443T>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000716 in 1,396,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ARHGAP42 NM_001367945.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• Publications: 0 publications found

Genes affected

ARHGAP42 (HGNC:26545): (Rho GTPase activating protein 42) This gene encodes a Rho GTPase-activating protein (RhoGAP), and member of the GRAF or BAR-PH family of proteins. Expression of this gene is enriched in vascular smooth muscle cells and the encoded protein inhibits RhoA activity to regulate vascular tone and control blood pressure. A mutation in the first intron of this gene modulates its expression and is associated with reduced blood pressure in human patients with borderline hypertension. [provided by RefSeq, Jul 2017]

ARHGAP42-AS1 (HGNC:54801): (ARHGAP42 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367945.1. 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
	ARHGAP42	NM_152432.4	MANE Select	c.140T>A	p.Ile47Asn	missense	Exon 1 of 24	NP_689645.2
	ARHGAP42	NM_001367945.1		c.-443T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 26	NP_001354874.1
	ARHGAP42	NM_001367945.1		c.-443T>A		5_prime_UTR	Exon 1 of 26	NP_001354874.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP42	ENST00000298815.13	TSL:5 MANE Select	c.140T>A	p.Ile47Asn	missense	Exon 1 of 24	ENSP00000298815.7	A6NI28
	ARHGAP42	ENST00000524892.7	TSL:5	c.140T>A	p.Ile47Asn	missense	Exon 1 of 23	ENSP00000431776.1	E9PJK4
	ARHGAP42-AS1	ENST00000501397.2	TSL:2	n.151A>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396284 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688694

African (AFR) AF: 0.00 AC: 0 AN: 31506

American (AMR) AF: 0.00 AC: 0 AN: 35528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25018

East Asian (EAS) AF: 0.00 AC: 0 AN: 35628

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077116

Other (OTH) AF: 0.00 AC: 0 AN: 57822

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.71
MutPred		0.58		Loss of stability (P = 0.0264)
MVP		0.25
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.055	Neutral
Varity_R		0.91
gMVP		0.92
Mutation Taster		=27/73	disease causing

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: rs1012498540; hg19: chr11-100558549;