NM_001005743.2:c.1175G>C

Variant names:

• chr14-73279346-C-G
• rs149035382
• NM_001005743.2:c.1175G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001005743.2(NUMB):​c.1175G>C​(p.Arg392Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R392H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• Publications: 2 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 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.1175G>C	p.Arg392Pro	missense	Exon 12 of 13	NP_001005743.1	P49757-1
	NUMB	NM_003744.6		c.1142G>C	p.Arg381Pro	missense	Exon 11 of 12	NP_003735.3
	NUMB	NM_001005744.2		c.1097-2053G>C		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.1175G>C	p.Arg392Pro	missense	Exon 12 of 13	ENSP00000451300.1	P49757-1
	NUMB	ENST00000557597.5	TSL:1	c.1142G>C	p.Arg381Pro	missense	Exon 11 of 12	ENSP00000451117.1	P49757-3
	NUMB	ENST00000556772.5	TSL:1	c.743G>C	p.Arg248Pro	missense	Exon 6 of 7	ENSP00000451513.1	G3V3Z8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250568 AF XY: 0.0000148

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: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461164 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726876

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111610

Other (OTH) AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.48		Gain of disorder (P = 0.0331)
MVP		0.76
MPC		0.73
ClinPred		0.76	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.60
Mutation Taster		=71/29	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: rs149035382; hg19: chr14-73746054;