7-50593090-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001350814.2(GRB10):c.1647C>T(p.Asp549=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,976 control chromosomes in the GnomAD database, including 9,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.082 (789 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8759 hom.)
• Consequence: GRB10 NM_001350814.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.798

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-50593090-G-A is Benign according to our data. Variant chr7-50593090-G-A is described in ClinVar as [Benign]. Clinvar id is 3060352.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.798 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRB10	NM_001350814.2	c.1647C>T	p.Asp549=	synonymous_variant	19/19	ENST00000401949.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRB10	ENST00000401949.6	c.1647C>T	p.Asp549=	synonymous_variant	19/19	1	NM_001350814.2	P3

Frequencies

GnomAD3 genomes AF: 0.0824 AC: 12530 AN: 152080 Hom.: 784 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0808

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0707

GnomAD3 exomes AF: 0.105 AC: 26225 AN: 248592 Hom.: 1836 AF XY: 0.107 AC XY: 14434 AN XY: 134932

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.0769

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.0953

Gnomad OTH exome AF: 0.0939

GnomAD4 exome AF: 0.102 AC: 149541 AN: 1461778 Hom.: 8759 Cov.: 32 AF XY: 0.103 AC XY: 74953 AN XY: 727200

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0472

Gnomad4 EAS exome AF: 0.0755

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.231

Gnomad4 NFE exome AF: 0.0994

Gnomad4 OTH exome AF: 0.0926

GnomAD4 genome AF: 0.0824 AC: 12538 AN: 152198 Hom.: 789 Cov.: 32 AF XY: 0.0916 AC XY: 6813 AN XY: 74382

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.0814

Gnomad4 ASJ AF: 0.0504

Gnomad4 EAS AF: 0.0724

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.0960

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0857 Hom.: 780

Bravo AF: 0.0682

Asia WGS AF: 0.0800 AC: 277 AN: 3478

EpiCase AF: 0.0859

EpiControl AF: 0.0850

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRB10-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.21
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs3807550; hg19: chr7-50660787; COSMIC: COSV60009967; COSMIC: COSV60009967;