14-73276665-T-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_001005743.2(NUMB):​c.1869A>C​(p.Leu623Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NUMB
NM_001005743.2 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.655

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.76
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NUMBNM_001005743.2 linkc.1869A>C p.Leu623Phe 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.1869A>C p.Leu623Phe missense_variant Exon 13 of 13 1 NM_001005743.2 ENSP00000451300.1 P49757-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727244
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
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:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000629
AC:
7
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.446
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
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
May 28, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1869A>C (p.L623F) alteration is located in exon 13 (coding exon 10) of the NUMB gene. This alteration results from a A to C substitution at nucleotide position 1869, causing the leucine (L) at amino acid position 623 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
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
.;.;.;D;.;.;.;D;T;.;.;.;.;.
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;.;.;.;D;.;.;D;D;D
M_CAP
Benign
0.079
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.41
T
MutationAssessor
Uncertain
2.4
.;.;.;M;.;.;.;M;.;.;.;.;.;.
PhyloP100
0.66
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.4
N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D;.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.018
D;D;D;D;T;D;D;D;D;D;T;T;T;T
Polyphen
1.0
D;D;D;D;.;D;D;D;.;D;.;.;.;.
Vest4
0.68
MutPred
0.20
.;.;.;Gain of methylation at K626 (P = 0.1847);.;.;.;Gain of methylation at K626 (P = 0.1847);.;.;.;.;.;.;
MVP
0.91
MPC
0.63
ClinPred
0.97
D
GERP RS
2.9
Varity_R
0.29
gMVP
0.43
Mutation Taster
=51/49
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: rs1594849615; hg19: chr14-73743373; API