7-50604017-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001350814.2(GRB10):c.1525C>G(p.Gln509Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 1,613,636 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (3 hom.)
• Consequence: GRB10 NM_001350814.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.79

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024909943).
• BP6: Variant 7-50604017-G-C is Benign according to our data. Variant chr7-50604017-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3043075.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRB10	NM_001350814.2	c.1525C>G	p.Gln509Glu	missense_variant	17/19	ENST00000401949.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRB10	ENST00000401949.6	c.1525C>G	p.Gln509Glu	missense_variant	17/19	1	NM_001350814.2	P3

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000585 AC: 146 AN: 249588 Hom.: 0 AF XY: 0.000716 AC XY: 97 AN XY: 135410

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000572 AC: 836 AN: 1461284 Hom.: 3 Cov.: 31 AF XY: 0.000646 AC XY: 470 AN XY: 727012

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000557

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74502

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000471 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000520 AC: 2

ESP6500EA AF: 0.000483 AC: 4

ExAC AF: 0.000869 AC: 105

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRB10-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2022

This variant is classified as likely 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.025	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N;N;N;N;.;.;N;N;N;N;.;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.061	T;T;T;T;.;.;T;D;T;T;.;T;.
Sift4G	Benign	0.075	T;T;T;T;.;.;T;T;T;T;.;T;.
Polyphen		0.048, 0.34, 0.15	.;B;.;.;.;.;.;B;B;.;.;.;B
Vest4		0.60
MVP		0.94
MPC		1.5
ClinPred		0.074	T
GERP RS		5.5
Varity_R		0.57
gMVP		0.63

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: rs201369855; hg19: chr7-50671714; COSMIC: COSV99047053; COSMIC: COSV99047053;