1-94174443-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004815.4(ARHGAP29):c.3212G>T(p.Gly1071Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ARHGAP29 NM_004815.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

Genes affected

ARHGAP29 (HGNC:30207): (Rho GTPase activating protein 29) Rap1 is a small GTPase that, through effectors, regulates Rho GTPase signaling. These effectors- Rasip1, Radil, and the protein encoded by this gene- translocate to the cell membrane, where they form a multiprotein complex. This complex is necessary for Rap1-induced inhibition of Rho signaling. Defects in this gene may be a cause of nonsyndromic cleft lip with or without cleft palate. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.115422934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP29	NM_004815.4	c.3212G>T	p.Gly1071Val	missense_variant	23/23	ENST00000260526.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP29	ENST00000260526.11	c.3212G>T	p.Gly1071Val	missense_variant	23/23	1	NM_004815.4	P1
ARHGAP29	ENST00000552844.5	c.3051+161G>T		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251344 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461884 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000940 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.3212G>T (p.G1071V) alteration is located in exon 23 (coding exon 22) of the ARHGAP29 gene. This alteration results from a G to T substitution at nucleotide position 3212, causing the glycine (G) at amino acid position 1071 to be replaced by a valine (V). 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	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Benign	0.85
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.051
Sift	Benign	0.16	T
Sift4G	Benign	0.19	T
Polyphen		0.41	B
Vest4		0.16
MVP		0.14
MPC		0.18
ClinPred		0.16	T
GERP RS		4.7
Varity_R		0.20
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761200097; hg19: chr1-94639999;