rs1114167282

Variant names:

• chr1-94184871-C-T
• rs1114167282
• NM_004815.4:c.2109+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004815.4(ARHGAP29):​c.2109+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000698 in 1,432,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ARHGAP29 NM_004815.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.07
• Publications: 3 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
• orofacial cleft

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04992076 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-94184871-C-T is Pathogenic according to our data. Variant chr1-94184871-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 242343.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004815.4. 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
	ARHGAP29	NM_004815.4	MANE Select	c.2109+1G>A		splice_donor intron	N/A	NP_004806.3
	ARHGAP29	NM_001328664.2		c.2109+1G>A		splice_donor intron	N/A	NP_001315593.1	Q52LW3-1
	ARHGAP29	NM_001328666.2		c.2082+1G>A		splice_donor intron	N/A	NP_001315595.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP29	ENST00000260526.11	TSL:1 MANE Select	c.2109+1G>A		splice_donor intron	N/A	ENSP00000260526.6	Q52LW3-1
	ARHGAP29	ENST00000482481.1	TSL:1	n.6685+1G>A		splice_donor intron	N/A
	ARHGAP29	ENST00000552844.5	TSL:1	n.2109+1G>A		splice_donor intron	N/A	ENSP00000449764.1	F8VWZ8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432110 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 712266

⚠️ 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: 31432

American (AMR) AF: 0.00 AC: 0 AN: 38170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39028

South Asian (SAS) AF: 0.00 AC: 0 AN: 81376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100042

Other (OTH) AF: 0.00 AC: 0 AN: 59004

⚠️ 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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Nonsyndromic cleft lip with or without cleft palate (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.1
GERP RS		4.3
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1114167282; hg19: chr1-94650427; COSMIC: COSV104590280;