7-50604095-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001350814.2(GRB10):c.1457-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,607,456 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (49 hom.)
• Consequence: GRB10 NM_001350814.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001196
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0300

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-50604095-G-A is Benign according to our data. Variant chr7-50604095-G-A is described in ClinVar as [Benign]. Clinvar id is 3043970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2095/152304) while in subpopulation AFR AF= 0.0477 (1982/41552). AF 95% confidence interval is 0.046. There are 46 homozygotes in gnomad4. There are 978 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2091 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRB10	NM_001350814.2	c.1457-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000401949.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRB10	ENST00000401949.6	c.1457-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001350814.2	P3

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2091 AN: 152186 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

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: 0.000176

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00377 AC: 940 AN: 249532 Hom.: 23 AF XY: 0.00278 AC XY: 376 AN XY: 135384

Gnomad AFR exome AF: 0.0531

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00145 AC: 2108 AN: 1455152 Hom.: 49 Cov.: 30 AF XY: 0.00123 AC XY: 890 AN XY: 724410

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000823

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.0138 AC: 2095 AN: 152304 Hom.: 46 Cov.: 33 AF XY: 0.0131 AC XY: 978 AN XY: 74462

Gnomad4 AFR AF: 0.0477

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0101 Hom.: 15

Bravo AF: 0.0158

Asia WGS AF: 0.00318 AC: 11 AN: 3478

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

Jun 13, 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	-0.86
Cadd	Benign	1.6
Dann	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs79207373; hg19: chr7-50671792;