14-73276696-A-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001005743.2(NUMB):​c.1838T>G​(p.Val613Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

NUMB
NM_001005743.2 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Publications

1 publications found
Variant links:
Genes affected
NUMB (HGNC:8060): (NUMB endocytic adaptor protein) The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03843838).
BS2
High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NUMBNM_001005743.2 linkc.1838T>G p.Val613Gly missense_variant Exon 13 of 13 ENST00000555238.6 NP_001005743.1 P49757-1A0A024R6F4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NUMBENST00000555238.6 linkc.1838T>G p.Val613Gly missense_variant Exon 13 of 13 1 NM_001005743.2 ENSP00000451300.1 P49757-1

Frequencies

GnomAD3 genomes
AF:
0.000269
AC:
41
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000868
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.000478
GnomAD2 exomes
AF:
0.0000795
AC:
20
AN:
251476
AF XY:
0.0000515
show subpopulations
Gnomad AFR exome
AF:
0.000985
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.000806
AC:
27
AN:
33480
American (AMR)
AF:
0.000112
AC:
5
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:
0.00
AC:
0
AN:
1112010
Other (OTH)
AF:
0.000132
AC:
8
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000269
AC:
41
AN:
152344
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.000866
AC:
36
AN:
41592
American (AMR)
AF:
0.000261
AC:
4
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.000473
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
3
5
8
10
13
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:
0.000481
Hom.:
0
Bravo
AF:
0.000378
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 15, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1838T>G (p.V613G) alteration is located in exon 13 (coding exon 10) of the NUMB gene. This alteration results from a T to G substitution at nucleotide position 1838, causing the valine (V) at amino acid position 613 to be replaced by a glycine (G). 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
0.11
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.50
.;.;.;D;.;.;.;D;T;.;.;.;.;.
Eigen
Benign
-0.18
Eigen_PC
Benign
0.022
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.83
T;T;T;T;T;.;.;.;T;.;.;T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.038
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
.;.;.;L;.;.;.;L;.;.;.;.;.;.
PhyloP100
4.1
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.8
N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.14
Sift
Uncertain
0.028
D;.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.51
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0050
B;B;B;B;.;B;B;B;.;B;.;.;.;.
Vest4
0.18
MVP
0.72
MPC
0.18
ClinPred
0.039
T
GERP RS
5.3
Varity_R
0.27
gMVP
0.30
Mutation Taster
=74/26
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: rs369160731; hg19: chr14-73743404; API