Genetic Variant DAB2IP:p.Gly77Ser (chr9-121699325-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001395010.1(DAB2IP):c.229G>A(p.Gly77Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000179 in 1,453,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DAB2IP
NM_001395010.1 missense, splice_region

Scores

Splicing: ADA: 0.9809

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.27

Variant links:

Genes affected

DAB2IP (HGNC:17294): (DAB2 interacting protein) DAB2IP is a Ras (MIM 190020) GTPase-activating protein (GAP) that acts as a tumor suppressor. The DAB2IP gene is inactivated by methylation in prostate and breast cancers (Yano et al., 2005 [PubMed 15386433]).[supplied by OMIM, May 2010]

DAB2IP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30744752).

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAB2IP	NM_001395010.1 link	c.229G>A	p.Gly77Ser	missense_variant, splice_region_variant	Exon 3 of 16	ENST00000408936.8	NP_001381939.1
DAB2IP	NM_032552.4 link	c.145G>A	p.Gly49Ser	missense_variant, splice_region_variant	Exon 3 of 17		NP_115941.2	Q5VWQ8-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DAB2IP	ENST00000408936.8 link	c.229G>A	p.Gly77Ser	missense_variant, splice_region_variant	Exon 3 of 16	5	NM_001395010.1	ENSP00000386183.3	Q5VWQ8-1
DAB2IP	ENST00000259371.7 link	c.145G>A	p.Gly49Ser	missense_variant, splice_region_variant	Exon 3 of 17	5		ENSP00000259371.2	Q5VWQ8-5
DAB2IP	ENST00000436835.6 link	n.144+20544G>A		intron_variant	Intron 2 of 5	3		ENSP00000409327.2	F6R503

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000572

AC:

AN:

174976

Hom.:

AF XY:

0.00

AC XY:

AN XY:

99228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000104

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1304822

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

648694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000737

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000215

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148514

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72394

show subpopulations

Gnomad4 AFR

AF:

0.0000245

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000198

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000843

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145G>A (p.G49S) alteration is located in exon 3 (coding exon 3) of the DAB2IP gene. This alteration results from a G to A substitution at nucleotide position 145, causing the glycine (G) at amino acid position 49 to be replaced by a serine (S). 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;.;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

.;.;L

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.21

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.27

T;T;T

Vest4

0.49, 0.50

MutPred

0.36

Gain of phosphorylation at G49 (P = 0.0252);Gain of phosphorylation at G49 (P = 0.0252);.;

MVP

0.56

MPC

1.3

ClinPred

0.77

GERP RS

3.1

Varity_R

0.34

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.69

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over