Genetic Variant NM_001350814.2:c.1429C>T (chr7-50604338-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001350814.2(GRB10):c.1429C>T(p.Pro477Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

GRB10
NM_001350814.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63

Variant links:

Genes affected

GRB10 (HGNC:4564): (growth factor receptor bound protein 10) 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. Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner, with expression observed from the paternal allele in the brain, and from the maternal allele in the placental trophoblasts. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2010]

GRB10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38988483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRB10	NM_001350814.2 link	c.1429C>T	p.Pro477Ser	missense_variant	Exon 16 of 19	ENST00000401949.6	NP_001337743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRB10	ENST00000401949.6 link	c.1429C>T	p.Pro477Ser	missense_variant	Exon 16 of 19	1	NM_001350814.2	ENSP00000385770.1		Q13322-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1429C>T (p.P477S) alteration is located in exon 13 (coding exon 13) of the GRB10 gene. This alteration results from a C to T substitution at nucleotide position 1429, causing the proline (P) at amino acid position 477 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;D;.;.;.;.;.;.;D;.;.;.;.

Eigen

Benign

0.085

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.;.;.;D;.;D;.;.;.;.;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.39

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.6

.;L;.;.;.;.;.;.;L;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.3

D;D;D;D;.;.;D;D;D;D;.;D;.

REVEL

Uncertain

0.42

Sift

Benign

0.11

T;T;T;T;.;.;T;T;T;T;.;T;.

Sift4G

Benign

0.20

T;T;T;T;.;.;T;T;T;T;.;T;.

Polyphen

0.0010, 0.0050

.;B;.;.;.;.;.;B;B;.;.;.;B

Vest4

0.46

MutPred

0.19

.;Loss of glycosylation at P477 (P = 0.0439);.;.;.;.;.;.;Loss of glycosylation at P477 (P = 0.0439);.;.;.;.;

MVP

0.92

MPC

0.91

ClinPred

0.97

GERP RS

5.2

Varity_R

0.27

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over