chr14-73284360-T-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001005743.2(NUMB):c.670A>G(p.Ile224Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 1 hom. )
Consequence
NUMB
NM_001005743.2 missense
NM_001005743.2 missense
Scores
2
15
Clinical Significance
Conservation
PhyloP100: 1.88
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.048208594).
BS2
?
High AC in GnomAdExome at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NUMB | NM_001005743.2 | c.670A>G | p.Ile224Val | missense_variant | 10/13 | ENST00000555238.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NUMB | ENST00000555238.6 | c.670A>G | p.Ile224Val | missense_variant | 10/13 | 1 | NM_001005743.2 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250144Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135144
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1460470Hom.: 1 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726264
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2023 | The c.670A>G (p.I224V) alteration is located in exon 10 (coding exon 7) of the NUMB gene. This alteration results from a A to G substitution at nucleotide position 670, causing the isoleucine (I) at amino acid position 224 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.;.;.;D;.;D;.;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;.;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T;.;.;.
Polyphen
B;B;B;B;B;B;B;.;B;.;.;.
Vest4
MutPred
0.21
.;Gain of phosphorylation at T221 (P = 0.0865);.;Gain of phosphorylation at T221 (P = 0.0865);Gain of phosphorylation at T221 (P = 0.0865);.;Gain of phosphorylation at T221 (P = 0.0865);.;Gain of phosphorylation at T221 (P = 0.0865);.;Gain of phosphorylation at T221 (P = 0.0865);Gain of phosphorylation at T221 (P = 0.0865);
MVP
MPC
0.62
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at