rs61756585

Variant names:

• chr7-50604057-G-A
• rs61756585
• NM_001350814.2:c.1485C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001350814.2(GRB10):​c.1485C>T​(p.His495His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,613,962 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (92 hom.)
• Consequence: GRB10 NM_001350814.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.326
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-50604057-G-A is Benign according to our data. Variant chr7-50604057-G-A is described in ClinVar as Benign. ClinVar VariationId is 2657500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.326 with no splicing effect.
• BS2: High AC in GnomAd4 at 1139 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350814.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRB10	NM_001350814.2	MANE Select	c.1485C>T	p.His495His	synonymous	Exon 17 of 19	NP_001337743.1	Q13322-1
	GRB10	NM_001371009.1		c.1632C>T	p.His544His	synonymous	Exon 14 of 16	NP_001357938.1
	GRB10	NM_001350815.2		c.1599C>T	p.His533His	synonymous	Exon 14 of 16	NP_001337744.1	A0A2R8YCL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRB10	ENST00000401949.6	TSL:1 MANE Select	c.1485C>T	p.His495His	synonymous	Exon 17 of 19	ENSP00000385770.1	Q13322-1
	GRB10	ENST00000398812.6	TSL:1	c.1485C>T	p.His495His	synonymous	Exon 14 of 16	ENSP00000381793.2	Q13322-1
	GRB10	ENST00000357271.9	TSL:1	c.1347C>T	p.His449His	synonymous	Exon 13 of 15	ENSP00000349818.5	Q13322-2

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1139 AN: 152210 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00815 AC: 2034 AN: 249582 AF XY: 0.00808

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00891

GnomAD4 exome AF: 0.00950 AC: 13883 AN: 1461634 Hom.: 92 Cov.: 31 AF XY: 0.00930 AC XY: 6761 AN XY: 727154

African (AFR) AF: 0.00176 AC: 59 AN: 33476

American (AMR) AF: 0.00561 AC: 251 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 385 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00307 AC: 265 AN: 86258

European-Finnish (FIN) AF: 0.0130 AC: 695 AN: 53414

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5768

European-Non Finnish (NFE) AF: 0.0104 AC: 11608 AN: 1111768

Other (OTH) AF: 0.00873 AC: 527 AN: 60394

GnomAD4 genome AF: 0.00748 AC: 1139 AN: 152328 Hom.: 5 Cov.: 33 AF XY: 0.00760 AC XY: 566 AN XY: 74486

African (AFR) AF: 0.00197 AC: 82 AN: 41564

American (AMR) AF: 0.00680 AC: 104 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 716 AN: 68034

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00960 Hom.: 7

Bravo AF: 0.00751

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0118

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	GRB10-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.8
DANN	Benign	0.61
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61756585; hg19: chr7-50671754; COSMIC: COSV60010655; COSMIC: COSV60010655;