NM_004490.3:c.1474C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004490.3(GRB14):c.1474C>T(p.Pro492Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,320 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

GRB14
NM_004490.3 missense, splice_region

Scores

Splicing: ADA: 0.9980

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

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]

GRB14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1474C>T	p.Pro492Ser	missense splice_region	Exon 13 of 14	NP_004481.2	Q14449-1
	GRB14	NM_001303422.2		c.1213C>T	p.Pro405Ser	missense splice_region	Exon 12 of 13	NP_001290351.1	Q14449-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRB14	ENST00000263915.8	TSL:1 MANE Select	c.1474C>T	p.Pro492Ser	missense splice_region	Exon 13 of 14	ENSP00000263915.3	Q14449-1
GRB14	ENST00000943514.1		c.1633C>T	p.Pro545Ser	missense splice_region	Exon 14 of 15	ENSP00000613573.1
GRB14	ENST00000943511.1		c.1621C>T	p.Pro541Ser	missense splice_region	Exon 14 of 15	ENSP00000613570.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250662

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.35e-7

AC:

AN:

1360320

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

682686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31494

American (AMR)

AF:

0.00

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25478

East Asian (EAS)

AF:

0.00

AC:

AN:

39128

South Asian (SAS)

AF:

0.00

AC:

AN:

84118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

9.81e-7

AC:

AN:

1019828

Other (OTH)

AF:

0.00

AC:

AN:

56818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.4

PhyloP100

8.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0020

Sift4G

Benign

0.069

Polyphen

1.0

Vest4

0.64

MutPred

0.38

Loss of catalytic residue at P492 (P = 0.0822)

MVP

0.94

MPC

0.30

ClinPred

0.99

GERP RS

5.4

Varity_R

0.87

gMVP

0.51

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over