1-161047887-C-A

Variant names:

• chr1-161047887-C-A
• rs759679526
• NM_001025598.2:c.3134G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001025598.2(ARHGAP30):​c.3134G>T​(p.Arg1045Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,406 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1045Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGAP30 NM_001025598.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 3 publications found

Genes affected

ARHGAP30 (HGNC:27414): (Rho GTPase activating protein 30) Predicted to enable GTPase activator activity. Predicted to be involved in small GTPase mediated signal transduction. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025598.2. 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
	ARHGAP30	NM_001025598.2	MANE Select	c.3134G>T	p.Arg1045Leu	missense	Exon 12 of 12	NP_001020769.1	Q7Z6I6-1
	ARHGAP30	NM_001287600.2		c.2690G>T	p.Arg897Leu	missense	Exon 11 of 11	NP_001274529.1	Q7Z6I6-3
	ARHGAP30	NM_001287602.2		c.2603G>T	p.Arg868Leu	missense	Exon 8 of 8	NP_001274531.1	A0A0A0MRJ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP30	ENST00000368013.8	TSL:2 MANE Select	c.3134G>T	p.Arg1045Leu	missense	Exon 12 of 12	ENSP00000356992.3	Q7Z6I6-1
	ARHGAP30	ENST00000368015.1	TSL:5	c.2603G>T	p.Arg868Leu	missense	Exon 8 of 8	ENSP00000356994.1	A0A0A0MRJ8
	ARHGAP30	ENST00000368016.7	TSL:5	c.2501G>T	p.Arg834Leu	missense	Exon 13 of 13	ENSP00000356995.3	A0A0A0MRJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248286 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 6.85e-7 AC: 1 AN: 1459406 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 725922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110828

Other (OTH) AF: 0.00 AC: 0 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.096
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.27		Loss of phosphorylation at S1040 (P = 0.154)
MVP		0.41
MPC		0.25
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.18
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs759679526; hg19: chr1-161017677;