5-39377273-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001343.4(DAB2):c.1514C>T(p.Thr505Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00151 in 1,609,264 control chromosomes in the GnomAD database, including 4 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 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: DAB2 NM_001343.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.65

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004726529).
• BP6: Variant 5-39377273-G-A is Benign according to our data. Variant chr5-39377273-G-A is described in ClinVar as [Benign]. Clinvar id is 782450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAB2	NM_001343.4	c.1514C>T	p.Thr505Ile	missense_variant	12/15	ENST00000320816.11
DAB2	NM_001244871.2	c.1451C>T	p.Thr484Ile	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAB2	ENST00000320816.11	c.1514C>T	p.Thr505Ile	missense_variant	12/15	1	NM_001343.4	P3
DAB2	ENST00000509337.5	c.1451C>T	p.Thr484Ile	missense_variant	10/13	1		A1
DAB2	ENST00000545653.5	c.1451C>T	p.Thr484Ile	missense_variant	11/14	5		A1
DAB2	ENST00000339788.10	c.860C>T	p.Thr287Ile	missense_variant	11/14	5

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00188 AC: 462 AN: 246230 Hom.: 2 AF XY: 0.00185 AC XY: 246 AN XY: 133008

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0141

Gnomad SAS exome AF: 0.000570

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00153 AC: 2229 AN: 1456986 Hom.: 3 Cov.: 34 AF XY: 0.00148 AC XY: 1070 AN XY: 724184

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0150

Gnomad4 SAS exome AF: 0.000748

Gnomad4 FIN exome AF: 0.000694

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74466

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00181 Hom.: 3

Bravo AF: 0.00175

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	20
Dann	Benign	0.89
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.34	T;T;T;.
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.036	D;T;T;D
Sift4G	Benign	0.082	T;T;T;T
Polyphen		0.041	B;.;B;B
Vest4		0.12
MVP		0.31
MPC		0.070
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.10
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145194026; hg19: chr5-39377375; COSMIC: COSV57917408; COSMIC: COSV57917408;