rs1485074137

Variant names:

• chr14-73284155-C-A
• rs1485074137
• NM_001005743.2:c.875G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-73284155-C-A
• chr14-73284155-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001005743.2(NUMB):​c.875G>T​(p.Arg292Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

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.875G>T	p.Arg292Leu	missense	Exon 10 of 13	NP_001005743.1	P49757-1
	NUMB	NM_003744.6		c.842G>T	p.Arg281Leu	missense	Exon 9 of 12	NP_003735.3
	NUMB	NM_001005744.2		c.875G>T	p.Arg292Leu	missense	Exon 10 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.875G>T	p.Arg292Leu	missense	Exon 10 of 13	ENSP00000451300.1	P49757-1
	NUMB	ENST00000557597.5	TSL:1	c.842G>T	p.Arg281Leu	missense	Exon 9 of 12	ENSP00000451117.1	P49757-3
	NUMB	ENST00000356296.8	TSL:1	c.875G>T	p.Arg292Leu	missense	Exon 10 of 12	ENSP00000348644.4	P49757-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.79		Loss of solvent accessibility (P = 0.0022)
MVP		0.92
MPC		2.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.69
Mutation Taster		=17/83	disease causing

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

dbSNP: rs1485074137; hg19: chr14-73750863;