chr14-73277269-C-A

Variant names:

• chr14-73277269-C-A
• NM_001005743.2:c.1265G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001005743.2(NUMB):​c.1265G>T​(p.Gly422Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.1265G>T	p.Gly422Val	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.1265G>T	p.Gly422Val	missense_variant	Exon 13 of 13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449862 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;.;.;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	0.018
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;.;.;.;D;.;.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	.;.;.;L;.;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.46	N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.35	T;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;D;T;T;T;D;T;D;T;T;D
Polyphen		0.99	D;D;D;P;.;D;D;P;.;D;.;.;.;.
Vest4		0.45
MutPred		0.21		.;.;.;Loss of glycosylation at S421 (P = 0.0271);.;.;.;Loss of glycosylation at S421 (P = 0.0271);.;.;.;.;.;.;
MVP		0.72
MPC		0.24
ClinPred		0.58	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-73743977;