dbSNP rs1114167282: ARHGAP29:c.2109+1G>A (chr1-94184871-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_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

Variant links:

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

ARHGAP29 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP29	NM_004815.4 link	c.2109+1G>A		splice_donor_variant, intron_variant	Intron 18 of 22	ENST00000260526.11	NP_004806.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ARHGAP29	ENST00000260526.11 link	c.2109+1G>A	splice_donor_variant, intron_variant	Intron 18 of 22	1	NM_004815.4	ENSP00000260526.6
ARHGAP29	ENST00000482481.1 link	n.6685+1G>A	splice_donor_variant, intron_variant	Intron 6 of 9	1
ARHGAP29	ENST00000552844.5 link	n.2109+1G>A	splice_donor_variant, intron_variant	Intron 18 of 25	1		ENSP00000449764.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712266

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31432

American (AMR)

AF:

0.00

AC:

AN:

38170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24824

East Asian (EAS)

AF:

0.00

AC:

AN:

39028

South Asian (SAS)

AF:

0.00

AC:

AN:

81376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5422

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100042

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nonsyndromic cleft lip with or without cleft palate

Pathogenic:1

Mar 25, 2016

Laboratorio de Genetica do Desenvolvimento - CEGH, Universidade de Sao Paulo

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.1

GERP RS

4.3

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over