rs1048854

Variant names:

• chr1-94177975-T-C
• rs1048854
• NM_004815.4:c.2673A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004815.4(ARHGAP29):​c.2673A>G​(p.Gln891Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,954 control chromosomes in the GnomAD database, including 51,897 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3793 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48104 hom.)
• Consequence: ARHGAP29 NM_004815.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397
• Publications: 18 publications found

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]

ARHGAP29 Gene-Disease associations (from GenCC):

• cleft lip with or without cleft palate

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=0.397 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP29	NM_004815.4	c.2673A>G	p.Gln891Gln	synonymous_variant	Exon 21 of 23	ENST00000260526.11	NP_004806.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP29	ENST00000260526.11	c.2673A>G	p.Gln891Gln	synonymous_variant	Exon 21 of 23	1	NM_004815.4	ENSP00000260526.6
ARHGAP29	ENST00000482481.1	n.7249A>G		non_coding_transcript_exon_variant	Exon 9 of 10	1
ARHGAP29	ENST00000552844.5	n.2673A>G		non_coding_transcript_exon_variant	Exon 21 of 26	1		ENSP00000449764.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29960 AN: 152030 Hom.: 3795 Cov.: 32

Gnomad AFR AF: 0.0662

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.219 AC: 55103 AN: 251332 AF XY: 0.225

Gnomad AFR exome AF: 0.0593

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.00266

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.249 AC: 364483 AN: 1461806 Hom.: 48104 Cov.: 35 AF XY: 0.249 AC XY: 181424 AN XY: 727206

African (AFR) AF: 0.0596 AC: 1997 AN: 33480

American (AMR) AF: 0.217 AC: 9701 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6944 AN: 26132

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39694

South Asian (SAS) AF: 0.201 AC: 17324 AN: 86258

European-Finnish (FIN) AF: 0.251 AC: 13385 AN: 53406

Middle Eastern (MID) AF: 0.348 AC: 2008 AN: 5768

European-Non Finnish (NFE) AF: 0.268 AC: 298524 AN: 1111952

Other (OTH) AF: 0.240 AC: 14523 AN: 60394

GnomAD4 genome AF: 0.197 AC: 29958 AN: 152148 Hom.: 3793 Cov.: 32 AF XY: 0.193 AC XY: 14387 AN XY: 74372

African (AFR) AF: 0.0663 AC: 2752 AN: 41538

American (AMR) AF: 0.221 AC: 3371 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3468

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5184

South Asian (SAS) AF: 0.183 AC: 883 AN: 4812

European-Finnish (FIN) AF: 0.248 AC: 2614 AN: 10558

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18339 AN: 67990

Other (OTH) AF: 0.232 AC: 491 AN: 2114

Alfa AF: 0.244 Hom.: 18140

Bravo AF: 0.190

Asia WGS AF: 0.0920 AC: 322 AN: 3478

EpiCase AF: 0.278

EpiControl AF: 0.278

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.9
DANN	Benign	0.47
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs1048854; hg19: chr1-94643531; COSMIC: COSV53108307;