NM_001005743.2:c.1252G>C

Variant names:

• chr14-73277282-C-G
• rs373974311
• NM_001005743.2:c.1252G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005743.2(NUMB):​c.1252G>C​(p.Gly418Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. G418C) 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: 0.650
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08382398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.1252G>C	p.Gly418Arg	missense_variant	Exon 13 of 13	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.1252G>C	p.Gly418Arg	missense_variant	Exon 13 of 13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;.;D;.;.;.;D;T;.;.;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;.;.;.;D;.;.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.084	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	.;.;.;L;.;.;.;L;.;.;.;.;.;.
PhyloP100		0.65
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.014	D;.;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.91	P;P;B;B;.;P;B;B;.;P;.;.;.;.
Vest4		0.26
MutPred		0.21		.;.;.;Gain of MoRF binding (P = 0.0363);.;.;.;Gain of MoRF binding (P = 0.0363);.;.;.;.;.;.;
MVP		0.71
MPC		0.22
ClinPred		0.24	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.29
Mutation Taster		=77/23	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: rs373974311; hg19: chr14-73743990;