2-164497267-C-A

Variant names:

• chr2-164497267-C-A
• rs150619313
• NM_004490.3:c.1238G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004490.3(GRB14):​c.1238G>T​(p.Arg413Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GRB14 NM_004490.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRB14	NM_004490.3	c.1238G>T	p.Arg413Leu	missense_variant	Exon 11 of 14	ENST00000263915.8	NP_004481.2
GRB14	NM_001303422.2	c.977G>T	p.Arg326Leu	missense_variant	Exon 10 of 13		NP_001290351.1
GRB14	XM_047444013.1	c.638G>T	p.Arg213Leu	missense_variant	Exon 10 of 13		XP_047299969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRB14	ENST00000263915.8	c.1238G>T	p.Arg413Leu	missense_variant	Exon 11 of 14	1	NM_004490.3	ENSP00000263915.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460986 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726780

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.67		Loss of MoRF binding (P = 0.0034);.;
MVP		0.85
MPC		0.40
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs150619313; hg19: chr2-165353777; COSMIC: COSV55737305; COSMIC: COSV55737305;