2-164508541-C-A

Variant names:

• chr2-164508541-C-A
• rs370149376
• NM_004490.3:c.937G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004490.3(GRB14):​c.937G>T​(p.Ala313Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GRB14 NM_004490.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00
• Publications: 0 publications found

Genes affected

GRB14 (HGNC:4565): (growth factor receptor bound protein 14) 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. This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor signaling. This gene may play a role in signaling pathways that regulate growth and metabolism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08786148).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004490.3. 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
	GRB14	NM_004490.3	MANE Select	c.937G>T	p.Ala313Ser	missense	Exon 8 of 14	NP_004481.2	Q14449-1
	GRB14	NM_001303422.2		c.676G>T	p.Ala226Ser	missense	Exon 7 of 13	NP_001290351.1	Q14449-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRB14	ENST00000263915.8	TSL:1 MANE Select	c.937G>T	p.Ala313Ser	missense	Exon 8 of 14	ENSP00000263915.3	Q14449-1
	GRB14	ENST00000446413.6	TSL:1	c.802G>T	p.Ala268Ser	missense	Exon 8 of 12	ENSP00000416786.2	C9JD37
	GRB14	ENST00000943514.1		c.937G>T	p.Ala313Ser	missense	Exon 8 of 15	ENSP00000613573.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250658 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461638 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

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	0.081
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.36	N
PhyloP100		1.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.16
Sift	Benign	0.89	T
Sift4G	Benign	0.63	T
Polyphen		0.0030	B
Vest4		0.30
MutPred		0.45		Loss of catalytic residue at A313 (P = 0.0201)
MVP		0.82
MPC		0.054
ClinPred		0.11	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.26
Mutation Taster		=79/21	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: rs370149376; hg19: chr2-165365051;