14-73289591-A-G

Position:

• chr14-73289591-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001005743.2(NUMB):​c.451-2277T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,158 control chromosomes in the GnomAD database, including 4,847 homozygotes. 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: 𝑓 0.23 (4847 hom., cov: 33)
• Consequence: NUMB NM_001005743.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.451-2277T>C		intron_variant		ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.451-2277T>C		intron_variant		1	NM_001005743.2	ENSP00000451300	P4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34685 AN: 152040 Hom.: 4834 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.228 AC: 34721 AN: 152158 Hom.: 4847 Cov.: 33 AF XY: 0.238 AC XY: 17681 AN XY: 74392

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.273

Alfa AF: 0.203 Hom.: 7967

Bravo AF: 0.241

Asia WGS AF: 0.389 AC: 1351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.4
DANN	Benign	0.42

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: rs10483853; hg19: chr14-73756299;