Genetic Variant GRB14:p.Asp447Gly (chr2-164497050-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004490.3(GRB14):c.1340A>G(p.Asp447Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D447V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GRB14
NM_004490.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.82

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRB14	NM_004490.3 link	c.1340A>G	p.Asp447Gly	missense_variant	Exon 12 of 14	ENST00000263915.8	NP_004481.2
GRB14	NM_001303422.2 link	c.1079A>G	p.Asp360Gly	missense_variant	Exon 11 of 13		NP_001290351.1	Q14449-2
GRB14	XM_047444013.1 link	c.740A>G	p.Asp247Gly	missense_variant	Exon 11 of 13		XP_047299969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRB14	ENST00000263915.8 link	c.1340A>G	p.Asp447Gly	missense_variant	Exon 12 of 14	1	NM_004490.3	ENSP00000263915.3		Q14449-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250876

AF XY:

0.00000738

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111860

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.8

L;.

PhyloP100

7.8

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.1

D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;.

Polyphen

0.44

B;.

Vest4

0.51

MutPred

0.44

Gain of MoRF binding (P = 0.029);.;

MVP

0.94

MPC

0.13

ClinPred

0.96

GERP RS

6.0

Varity_R

0.81

gMVP

0.45

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over