14-73277093-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005743.2(NUMB):c.1441C>T(p.Pro481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.768

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10132843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUMB	NM_001005743.2	c.1441C>T	p.Pro481Ser	missense_variant	13/13	ENST00000555238.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUMB	ENST00000555238.6	c.1441C>T	p.Pro481Ser	missense_variant	13/13	1	NM_001005743.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251206 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135764

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.1441C>T (p.P481S) alteration is located in exon 13 (coding exon 10) of the NUMB gene. This alteration results from a C to T substitution at nucleotide position 1441, causing the proline (P) at amino acid position 481 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	19
Dann	Benign	0.93
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T;T;T;T;T;.;.;.;T;.;.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D;.;N;N;D;D;N;N;N;D;D;D;D;D
REVEL	Benign	0.024
Sift	Benign	0.043	D;.;D;D;D;D;D;D;T;D;D;D;D;D
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.;B;B;B;.;B;.;.;.;.
Vest4		0.081
MutPred		0.21		.;.;.;Loss of glycosylation at S480 (P = 0.1013);.;.;.;Loss of glycosylation at S480 (P = 0.1013);.;.;.;.;.;.;
MVP		0.57
MPC		0.14
ClinPred		0.055	T
GERP RS		2.7
Varity_R		0.050
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs1247245133; hg19: chr14-73743801;