rs148278687

Variant names:

• chr14-73279391-G-A
• rs148278687
• NM_001005743.2:c.1130C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-73279391-G-A
• chr14-73279391-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001005743.2(NUMB):​c.1130C>T​(p.Ala377Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000218 in 1,601,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A377D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.40
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16813242).
• BS2: High AC in GnomAd4 at 18 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.1130C>T	p.Ala377Val	missense	Exon 12 of 13	NP_001005743.1	P49757-1
	NUMB	NM_003744.6		c.1097C>T	p.Ala366Val	missense	Exon 11 of 12	NP_003735.3
	NUMB	NM_001005744.2		c.1097-2098C>T		intron	N/A	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.1130C>T	p.Ala377Val	missense	Exon 12 of 13	ENSP00000451300.1	P49757-1
	NUMB	ENST00000557597.5	TSL:1	c.1097C>T	p.Ala366Val	missense	Exon 11 of 12	ENSP00000451117.1	P49757-3
	NUMB	ENST00000556772.5	TSL:1	c.698C>T	p.Ala233Val	missense	Exon 6 of 7	ENSP00000451513.1	G3V3Z8

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152258 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00 AC: 0 AN: 237156 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1449574 Hom.: 0 Cov.: 31 AF XY: 0.00000972 AC XY: 7 AN XY: 720450

African (AFR) AF: 0.0000302 AC: 1 AN: 33080

American (AMR) AF: 0.000234 AC: 10 AN: 42670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25206

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 84164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106314

Other (OTH) AF: 0.000100 AC: 6 AN: 59882

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00105 AC: 16 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68052

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000355

ClinVar

ClinVar submissions

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	Benign	0.10
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Benign	0.37	T
Polyphen		0.91	P
Vest4		0.21
MutPred		0.35		Gain of methylation at K378 (P = 0.0351)
MVP		0.64
MPC		0.14
ClinPred		0.37	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.43
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs148278687; hg19: chr14-73746099;