2-164497030-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004490.3(GRB14):​c.1360A>T​(p.Ile454Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,613,768 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 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

GRB14
NM_004490.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

Publications

2 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.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07047567).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRB14NM_004490.3 linkc.1360A>T p.Ile454Phe missense_variant Exon 12 of 14 ENST00000263915.8 NP_004481.2
GRB14NM_001303422.2 linkc.1099A>T p.Ile367Phe missense_variant Exon 11 of 13 NP_001290351.1 Q14449-2
GRB14XM_047444013.1 linkc.760A>T p.Ile254Phe missense_variant Exon 11 of 13 XP_047299969.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRB14ENST00000263915.8 linkc.1360A>T p.Ile454Phe missense_variant Exon 12 of 14 1 NM_004490.3 ENSP00000263915.3 Q14449-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000865
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:
0.000120
AC:
30
AN:
250752
AF XY:
0.000111
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00149
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000133
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000876
AC:
128
AN:
1461562
Hom.:
0
Cov.:
31
AF XY:
0.0000963
AC XY:
70
AN XY:
727100
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33468
American (AMR)
AF:
0.0000224
AC:
1
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00226
AC:
59
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39670
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000504
AC:
56
AN:
1111788
Other (OTH)
AF:
0.000182
AC:
11
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
7
14
21
28
35
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000460
AC:
7
AN:
152206
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74354
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.000865
AC:
3
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
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:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.511
Heterozygous variant carriers
0
1
2
2
3
4
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:
0.000315
Hom.:
0
Bravo
AF:
0.0000945
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 22, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1360A>T (p.I454F) alteration is located in exon 12 (coding exon 12) of the GRB14 gene. This alteration results from a A to T substitution at nucleotide position 1360, causing the isoleucine (I) at amino acid position 454 to be replaced by a phenylalanine (F). 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
Benign
0.071
BayesDel_addAF
Benign
-0.077
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
18
DANN
Benign
0.92
DEOGEN2
Benign
0.33
T;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.075
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.80
T;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.070
T;T
MetaSVM
Uncertain
-0.090
T
MutationAssessor
Benign
1.3
L;.
PhyloP100
1.6
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.49
N;N
REVEL
Benign
0.27
Sift
Benign
0.14
T;T
Sift4G
Benign
0.71
T;.
Polyphen
0.037
B;.
Vest4
0.33
MVP
0.86
MPC
0.10
ClinPred
0.059
T
GERP RS
3.4
Varity_R
0.27
gMVP
0.17
Mutation Taster
=82/18
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs145405254; hg19: chr2-165353540; API