chr7-50616226-G-C

Variant names:

• chr7-50616226-G-C
• rs200796219
• NM_001350814.2:c.968C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001350814.2(GRB10):​c.968C>G​(p.Thr323Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GRB10 NM_001350814.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.15
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 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.968C>G	p.Thr323Ser	missense	Exon 11 of 19	NP_001337743.1	Q13322-1
	GRB10	NM_001371009.1		c.1115C>G	p.Thr372Ser	missense	Exon 8 of 16	NP_001357938.1
	GRB10	NM_001350815.2		c.1082C>G	p.Thr361Ser	missense	Exon 8 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.968C>G	p.Thr323Ser	missense	Exon 11 of 19	ENSP00000385770.1	Q13322-1
	GRB10	ENST00000398812.6	TSL:1	c.968C>G	p.Thr323Ser	missense	Exon 8 of 16	ENSP00000381793.2	Q13322-1
	GRB10	ENST00000335866.7	TSL:1	c.794C>G	p.Thr265Ser	missense	Exon 9 of 17	ENSP00000338543.3	Q13322-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.34
Sift	Benign	0.11	T
Sift4G	Uncertain	0.055	T
Polyphen		0.37	B
Vest4		0.45
MutPred		0.35		Gain of disorder (P = 0.0394)
MVP		0.89
MPC		0.84
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.26
Mutation Taster		=49/51	disease causing

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: rs200796219; hg19: chr7-50683923;