2-164493166-T-G

Position:

• chr2-164493166-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004490.3(GRB14):​c.1493A>C​(p.Glu498Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRB14 NM_004490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18670404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRB14	NM_004490.3	c.1493A>C	p.Glu498Ala	missense_variant	14/14	ENST00000263915.8	NP_004481.2
GRB14	NM_001303422.2	c.1232A>C	p.Glu411Ala	missense_variant	13/13		NP_001290351.1
GRB14	XM_047444013.1	c.893A>C	p.Glu298Ala	missense_variant	13/13		XP_047299969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRB14	ENST00000263915.8	c.1493A>C	p.Glu498Ala	missense_variant	14/14	1	NM_004490.3	ENSP00000263915
GRB14	ENST00000696453.2	c.1232A>C	p.Glu411Ala	missense_variant	13/13			ENSP00000512640	P1
GRB14	ENST00000488342.5	n.1629A>C		non_coding_transcript_exon_variant	14/14	5
GRB14	ENST00000497306.1	n.62A>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2023

The c.1493A>C (p.E498A) alteration is located in exon 14 (coding exon 14) of the GRB14 gene. This alteration results from a A to C substitution at nucleotide position 1493, causing the glutamic acid (E) at amino acid position 498 to be replaced by an alanine (A). 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	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.056	T
Sift4G	Uncertain	0.019	D
Polyphen		0.013	B
Vest4		0.12
MutPred		0.56		Loss of disorder (P = 0.0506);
MVP		0.59
MPC		0.061
ClinPred		0.79	D
GERP RS		0.040
Varity_R		0.39
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-165349676;