Variant 2-164508502-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004490.3(GRB14):c.976G>C(p.Glu326Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GRB14
NM_004490.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.42

Variant links:

Genes affected

GRB14 (HGNC:4565): (growth factor receptor bound protein 14) The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor signaling. This gene may play a role in signaling pathways that regulate growth and metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

GRB14 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRB14	NM_004490.3 linkuse as main transcript	c.976G>C	p.Glu326Gln	missense_variant	8/14	ENST00000263915.8	NP_004481.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRB14	ENST00000263915.8 linkuse as main transcript	c.976G>C	p.Glu326Gln	missense_variant	8/14	1	NM_004490.3	ENSP00000263915		Q14449-1
GRB14	ENST00000446413.6 linkuse as main transcript	c.841G>C	p.Glu281Gln	missense_variant	8/12	1		ENSP00000416786
GRB14	ENST00000696453.2 linkuse as main transcript	c.715G>C	p.Glu239Gln	missense_variant	7/13			ENSP00000512640	P1	Q14449-2
GRB14	ENST00000488342.5 linkuse as main transcript	n.1112G>C		non_coding_transcript_exon_variant	8/14	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250918

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

The c.976G>C (p.E326Q) alteration is located in exon 8 (coding exon 8) of the GRB14 gene. This alteration results from a G to C substitution at nucleotide position 976, causing the glutamic acid (E) at amino acid position 326 to be replaced by a glutamine (Q). 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

Benign

0.24

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

0.94

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.085

T;.

Polyphen

0.77

P;.

Vest4

0.51

MutPred

0.54

Gain of catalytic residue at E326 (P = 0.0137);.;

MVP

0.87

MPC

0.13

ClinPred

0.67

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.69

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.28

Position offset: -47

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