7-50595451-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001350814.2(GRB10):​c.1624T>A​(p.Phe542Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GRB10
NM_001350814.2 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRB10NM_001350814.2 linkuse as main transcriptc.1624T>A p.Phe542Ile missense_variant 18/19 ENST00000401949.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRB10ENST00000401949.6 linkuse as main transcriptc.1624T>A p.Phe542Ile missense_variant 18/191 NM_001350814.2 P3Q13322-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

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 GeneticsNov 17, 2022The c.1624T>A (p.F542I) alteration is located in exon 15 (coding exon 15) of the GRB10 gene. This alteration results from a T to A substitution at nucleotide position 1624, causing the phenylalanine (F) at amino acid position 542 to be replaced by an isoleucine (I). 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
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
.;D;.;.;.;.;.;.;D;.;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;.;.;.;D;.;D;.;.;.;.;D
M_CAP
Uncertain
0.093
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
1.0
.;L;.;.;.;.;.;.;L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-4.8
D;D;D;D;.;.;D;D;D;D;.;D;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0070
D;D;D;D;.;.;D;D;D;D;.;D;.
Sift4G
Uncertain
0.052
T;D;T;T;.;.;T;T;D;T;.;T;.
Polyphen
0.98, 1.0
.;D;.;.;.;.;.;D;D;.;.;.;D
Vest4
0.61
MutPred
0.83
.;Gain of methylation at K540 (P = 0.1011);.;.;.;.;.;.;Gain of methylation at K540 (P = 0.1011);.;.;.;.;
MVP
0.97
MPC
1.9
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.74
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr7-50663148; API