rs1114167280

Variant names:

• chr1-94203995-C-G
• rs1114167280
• NM_004815.4:c.698-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004815.4(ARHGAP29):​c.698-1G>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ARHGAP29 NM_004815.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.31
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-94203995-C-G is Pathogenic according to our data. Variant chr1-94203995-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 242341.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.698-1G>C		splice_acceptor intron	N/A	NP_004806.3
	ARHGAP29	NM_001328664.2		c.698-1G>C		splice_acceptor intron	N/A	NP_001315593.1	Q52LW3-1
	ARHGAP29	NM_001328666.2		c.698-1G>C		splice_acceptor 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.698-1G>C		splice_acceptor intron	N/A	ENSP00000260526.6	Q52LW3-1
	ARHGAP29	ENST00000370217.3	TSL:1	c.698-1G>C		splice_acceptor intron	N/A	ENSP00000359237.3	Q52LW3-2
	ARHGAP29	ENST00000552844.5	TSL:1	n.698-1G>C		splice_acceptor intron	N/A	ENSP00000449764.1	F8VWZ8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.3
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs1114167280; hg19: chr1-94669551;