2-164494488-T-G

Variant summary

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

The NM_004490.3(GRB14):​c.1419A>C​(p.Lys473Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000873 in 1,603,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

GRB14
NM_004490.3 missense

Scores

12
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRB14NM_004490.3 linkc.1419A>C p.Lys473Asn missense_variant Exon 13 of 14 ENST00000263915.8 NP_004481.2
GRB14NM_001303422.2 linkc.1158A>C p.Lys386Asn missense_variant Exon 12 of 13 NP_001290351.1 Q14449-2
GRB14XM_047444013.1 linkc.819A>C p.Lys273Asn missense_variant Exon 12 of 13 XP_047299969.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRB14ENST00000263915.8 linkc.1419A>C p.Lys473Asn missense_variant Exon 13 of 14 1 NM_004490.3 ENSP00000263915.3 Q14449-1
GRB14ENST00000696453.2 linkc.1158A>C p.Lys386Asn missense_variant Exon 12 of 13 ENSP00000512640.1 Q14449-2
GRB14ENST00000488342.5 linkn.1555A>C non_coding_transcript_exon_variant Exon 13 of 14 5
GRB14ENST00000497306.1 linkn.46-1306A>C intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251064
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000930
AC:
135
AN:
1451230
Hom.:
0
Cov.:
26
AF XY:
0.0000927
AC XY:
67
AN XY:
722816
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33254
American (AMR)
AF:
0.00
AC:
0
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26060
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39550
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86044
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.000120
AC:
132
AN:
1102504
Other (OTH)
AF:
0.0000500
AC:
3
AN:
59964
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.443
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.435
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 13, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1419A>C (p.K473N) alteration is located in exon 13 (coding exon 13) of the GRB14 gene. This alteration results from a A to C substitution at nucleotide position 1419, causing the lysine (K) at amino acid position 473 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.038
D
MetaRNN
Uncertain
0.47
T
MetaSVM
Uncertain
0.16
D
MutationAssessor
Benign
0.90
L
PhyloP100
2.3
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.32
Sift
Uncertain
0.026
D
Sift4G
Uncertain
0.022
D
Polyphen
0.95
P
Vest4
0.48
MutPred
0.48
Loss of catalytic residue at K473 (P = 0.0018);
MVP
0.89
MPC
0.11
ClinPred
0.52
D
GERP RS
5.4
Varity_R
0.58
gMVP
0.59
Mutation Taster
=67/33
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

Publications

Other links and lift over

dbSNP: rs760727704; hg19: chr2-165350998; API