chr14-73276665-T-G

Variant names:

• chr14-73276665-T-G
• rs1594849615
• NM_001005743.2:c.1869A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001005743.2(NUMB):​c.1869A>C​(p.Leu623Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.655
• 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.1869A>C	p.Leu623Phe	missense	Exon 13 of 13	NP_001005743.1	P49757-1
	NUMB	NM_003744.6		c.1836A>C	p.Leu612Phe	missense	Exon 12 of 12	NP_003735.3
	NUMB	NM_001005744.2		c.1725A>C	p.Leu575Phe	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.1869A>C	p.Leu623Phe	missense	Exon 13 of 13	ENSP00000451300.1	P49757-1
	NUMB	ENST00000557597.5	TSL:1	c.1836A>C	p.Leu612Phe	missense	Exon 12 of 12	ENSP00000451117.1	P49757-3
	NUMB	ENST00000356296.8	TSL:1	c.1725A>C	p.Leu575Phe	missense	Exon 12 of 12	ENSP00000348644.4	P49757-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.66
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.20		Gain of methylation at K626 (P = 0.1847)
MVP		0.91
MPC		0.63
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.29
gMVP		0.43
Mutation Taster		=51/49	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

dbSNP: rs1594849615; hg19: chr14-73743373;