14-73277195-C-T

Position:

• chr14-73277195-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001005743.2(NUMB):​c.1339G>A​(p.Val447Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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]

NUMB (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.1339G>A	p.Val447Met	missense_variant	13/13	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.1339G>A	p.Val447Met	missense_variant	13/13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.1339G>A (p.V447M) alteration is located in exon 13 (coding exon 10) of the NUMB gene. This alteration results from a G to A substitution at nucleotide position 1339, causing the valine (V) at amino acid position 447 to be replaced by a methionine (M). 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;.;D;.;.;.;D;T;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;.;.;.;D;.;.;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T;T;T;T;T;D;T;T;T;T;T
Polyphen		1.0	D;D;D;D;.;D;D;D;.;D;.;.;.;.
Vest4		0.67
MutPred		0.14		.;.;.;Gain of ubiquitination at K449 (P = 0.0846);.;.;.;Gain of ubiquitination at K449 (P = 0.0846);.;.;.;.;.;.;
MVP		0.87
MPC		0.61
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-73743903;