5-39377028-T-C

Position:

• chr5-39377028-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001343.4(DAB2):​c.1759A>G​(p.Thr587Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,028 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (65 hom.)
• Consequence: DAB2 NM_001343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.203

Genes affected

DAB2 (HGNC:2662): (DAB adaptor protein 2) This gene encodes a mitogen-responsive phosphoprotein. It is expressed in normal ovarian epithelial cells, but is down-regulated or absent from ovarian carcinoma cell lines, suggesting its role as a tumor suppressor. This protein binds to the SH3 domains of GRB2, an adaptor protein that couples tyrosine kinase receptors to SOS (a guanine nucleotide exchange factor for Ras), via its C-terminal proline-rich sequences, and may thus modulate growth factor/Ras pathways by competing with SOS for binding to GRB2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025002956).
• BP6: Variant 5-39377028-T-C is Benign according to our data. Variant chr5-39377028-T-C is described in ClinVar as [Benign]. Clinvar id is 712448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAB2	NM_001343.4	c.1759A>G	p.Thr587Ala	missense_variant	12/15	ENST00000320816.11	NP_001334.2
DAB2	NM_001244871.2	c.1696A>G	p.Thr566Ala	missense_variant	11/14		NP_001231800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAB2	ENST00000320816.11	c.1759A>G	p.Thr587Ala	missense_variant	12/15	1	NM_001343.4	ENSP00000313391	P3
DAB2	ENST00000509337.5	c.1696A>G	p.Thr566Ala	missense_variant	10/13	1		ENSP00000426245	A1
DAB2	ENST00000545653.5	c.1696A>G	p.Thr566Ala	missense_variant	11/14	5		ENSP00000439919	A1
DAB2	ENST00000339788.10	c.1105A>G	p.Thr369Ala	missense_variant	11/14	5		ENSP00000345508

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2351 AN: 152042 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00417 AC: 1047 AN: 251146 Hom.: 29 AF XY: 0.00295 AC XY: 401 AN XY: 135720

Gnomad AFR exome AF: 0.0582

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00158 AC: 2308 AN: 1461868 Hom.: 65 Cov.: 34 AF XY: 0.00134 AC XY: 977 AN XY: 727242

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.0155 AC: 2357 AN: 152160 Hom.: 54 Cov.: 32 AF XY: 0.0152 AC XY: 1129 AN XY: 74396

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00261 Hom.: 22

Bravo AF: 0.0181

ESP6500AA AF: 0.0508 AC: 224

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00490 AC: 595

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.89
DANN	Benign	0.83
DEOGEN2	Benign	0.32	.;.;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.55	T;T;T;.
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.66	N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.42	T;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.041
MVP		0.30
MPC		0.064
ClinPred		0.00017	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs75610108; hg19: chr5-39377130;