7-50606346-C-T

Variant names:

• chr7-50606346-C-T
• rs61734187
• NM_001350814.2:c.1263G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001350814.2(GRB10):​c.1263G>A​(p.Ser421Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,726 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (12 hom.)
• Consequence: GRB10 NM_001350814.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.994
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-50606346-C-T is Benign according to our data. Variant chr7-50606346-C-T is described in ClinVar as Benign. ClinVar VariationId is 3052388.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.994 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00582 (887/152314) while in subpopulation AFR AF = 0.0196 (814/41566). AF 95% confidence interval is 0.0185. There are 11 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 887 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.1263G>A	p.Ser421Ser	synonymous	Exon 14 of 19	NP_001337743.1	Q13322-1
	GRB10	NM_001371009.1		c.1410G>A	p.Ser470Ser	synonymous	Exon 11 of 16	NP_001357938.1
	GRB10	NM_001350815.2		c.1377G>A	p.Ser459Ser	synonymous	Exon 11 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.1263G>A	p.Ser421Ser	synonymous	Exon 14 of 19	ENSP00000385770.1	Q13322-1
	GRB10	ENST00000398812.6	TSL:1	c.1263G>A	p.Ser421Ser	synonymous	Exon 11 of 16	ENSP00000381793.2	Q13322-1
	GRB10	ENST00000357271.9	TSL:1	c.1125G>A	p.Ser375Ser	synonymous	Exon 10 of 15	ENSP00000349818.5	Q13322-2

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 885 AN: 152196 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00160 AC: 400 AN: 249578 AF XY: 0.00129

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000859 AC: 1256 AN: 1461412 Hom.: 12 Cov.: 30 AF XY: 0.000783 AC XY: 569 AN XY: 727060

African (AFR) AF: 0.0211 AC: 706 AN: 33462

American (AMR) AF: 0.00112 AC: 50 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000363 AC: 403 AN: 1111590

Other (OTH) AF: 0.00144 AC: 87 AN: 60382

GnomAD4 genome AF: 0.00582 AC: 887 AN: 152314 Hom.: 11 Cov.: 32 AF XY: 0.00549 AC XY: 409 AN XY: 74472

African (AFR) AF: 0.0196 AC: 814 AN: 41566

American (AMR) AF: 0.00281 AC: 43 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00282 Hom.: 5

Bravo AF: 0.00623

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GRB10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.41
DANN	Benign	0.51
PhyloP100		-0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61734187; hg19: chr7-50674043;