14-73277195-C-T

Variant names:

• chr14-73277195-C-T
• NM_001005743.2:c.1339G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005743.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMB	NM_001005743.2	MANE Select	c.1339G>A	p.Val447Met	missense	Exon 13 of 13	NP_001005743.1	P49757-1
	NUMB	NM_003744.6		c.1306G>A	p.Val436Met	missense	Exon 12 of 12	NP_003735.3
	NUMB	NM_001005744.2		c.1195G>A	p.Val399Met	missense	Exon 12 of 12	NP_001005744.1	P49757-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMB	ENST00000555238.6	TSL:1 MANE Select	c.1339G>A	p.Val447Met	missense	Exon 13 of 13	ENSP00000451300.1	P49757-1
	NUMB	ENST00000557597.5	TSL:1	c.1306G>A	p.Val436Met	missense	Exon 12 of 12	ENSP00000451117.1	P49757-3
	NUMB	ENST00000356296.8	TSL:1	c.1195G>A	p.Val399Met	missense	Exon 12 of 12	ENSP00000348644.4	P49757-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.14		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
Mutation Taster		=78/22	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: chr14-73743903;