7-50605298-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001350814.2(GRB10):​c.1381G>A​(p.Ala461Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,611,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GRB10
NM_001350814.2 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.73
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRB10NM_001350814.2 linkuse as main transcriptc.1381G>A p.Ala461Thr missense_variant 15/19 ENST00000401949.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRB10ENST00000401949.6 linkuse as main transcriptc.1381G>A p.Ala461Thr missense_variant 15/191 NM_001350814.2 P3Q13322-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1459540
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
726266
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000189
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

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 submitterclinical testingAmbry GeneticsJun 07, 2024The c.1381G>A (p.A461T) alteration is located in exon 12 (coding exon 12) of the GRB10 gene. This alteration results from a G to A substitution at nucleotide position 1381, causing the alanine (A) at amino acid position 461 to be replaced by a threonine (T). 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
0.11
BayesDel_addAF
Benign
-0.020
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
.;D;.;.;.;.;.;.;D;.;.;.;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D;D;.;.;.;D;.;D;.;.;.;.;D
M_CAP
Benign
0.047
D
MetaRNN
Uncertain
0.59
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Benign
0.92
.;L;.;.;.;.;.;.;L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-2.3
N;N;N;N;.;.;N;N;N;N;.;N;.
REVEL
Uncertain
0.45
Sift
Benign
0.12
T;T;T;T;.;.;T;T;T;T;.;T;.
Sift4G
Benign
0.19
T;T;T;T;.;.;T;T;T;T;.;T;.
Polyphen
0.35, 0.62
.;B;.;.;.;.;.;P;B;.;.;.;P
Vest4
0.35
MutPred
0.80
.;Loss of catalytic residue at A461 (P = 0.0436);.;.;.;.;.;.;Loss of catalytic residue at A461 (P = 0.0436);.;.;.;.;
MVP
0.93
MPC
0.99
ClinPred
0.60
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.18
gMVP
0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2048337757; hg19: chr7-50672995; COSMIC: COSV60015419; API