chr14-73277147-G-C

Variant names:

• chr14-73277147-G-C
• NM_001005743.2:c.1387C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005743.2(NUMB):​c.1387C>G​(p.Leu463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038004696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.1387C>G	p.Leu463Val	missense_variant	Exon 13 of 13	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.1387C>G	p.Leu463Val	missense_variant	Exon 13 of 13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1387C>G (p.L463V) alteration is located in exon 13 (coding exon 10) of the NUMB gene. This alteration results from a C to G substitution at nucleotide position 1387, causing the leucine (L) at amino acid position 463 to be replaced by a valine (V). 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	0.061
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.27	.;.;.;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T;T;T;.;.;.;T;.;.;T;T;T
M_CAP	Benign	0.013	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	0.55	.;.;.;N;.;.;.;N;.;.;.;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.11	N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.084
Sift	Benign	0.88	T;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.27	B;B;B;B;.;B;B;B;.;B;.;.;.;.
Vest4		0.22
MutPred		0.042		.;.;.;Loss of glycosylation at P462 (P = 0.0893);.;.;.;Loss of glycosylation at P462 (P = 0.0893);.;.;.;.;.;.;
MVP		0.42
MPC		0.14
ClinPred		0.084	T
GERP RS		2.8
Varity_R		0.039
gMVP		0.20
Mutation Taster		=88/12	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

Other links and lift over

hg19: chr14-73743855;