chr14-73284302-G-T

Position:

• chr14-73284302-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM2 BP4_Moderate BS2

The NM_001005743.2(NUMB):​c.728C>A​(p.Thr243Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 0.0000034 (0 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.49

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]

NUMB (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity NUMB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2567247).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.728C>A	p.Thr243Asn	missense_variant	10/13	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.728C>A	p.Thr243Asn	missense_variant	10/13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.55	.;.;.;D;.;.;D;T;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;.;.;D;.;D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	.;L;.;L;L;.;L;.;L;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.61	N;.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.32	T;.;T;T;T;T;T;T;T;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.73	P;P;P;B;P;P;B;.;P;.;.;.
Vest4		0.27
MutPred		0.19		.;Loss of glycosylation at T243 (P = 0.0015);.;Loss of glycosylation at T243 (P = 0.0015);Loss of glycosylation at T243 (P = 0.0015);.;Loss of glycosylation at T243 (P = 0.0015);.;Loss of glycosylation at T243 (P = 0.0015);.;Loss of glycosylation at T243 (P = 0.0015);Loss of glycosylation at T243 (P = 0.0015);
MVP		0.74
MPC		1.0
ClinPred		0.74	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.24

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: rs1050477; hg19: chr14-73751010;