14-73330961-G-T

Variant names:

• chr14-73330961-G-T
• rs12435797
• NM_001005743.2:c.127-7757C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001005743.2(NUMB):​c.127-7757C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,002 control chromosomes in the GnomAD database, including 8,264 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 0.31 (8264 hom., cov: 32)
• Consequence: NUMB NM_001005743.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.916
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.127-7757C>A		intron_variant	Intron 4 of 12	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.127-7757C>A		intron_variant	Intron 4 of 12	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46705 AN: 151886 Hom.: 8249 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.696

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.349

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

GnomAD4 genome AF: 0.308 AC: 46756 AN: 152002 Hom.: 8264 Cov.: 32 AF XY: 0.315 AC XY: 23378 AN XY: 74310

African (AFR) AF: 0.399 AC: 16531 AN: 41446

American (AMR) AF: 0.400 AC: 6107 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3466

East Asian (EAS) AF: 0.696 AC: 3593 AN: 5162

South Asian (SAS) AF: 0.277 AC: 1331 AN: 4812

European-Finnish (FIN) AF: 0.257 AC: 2715 AN: 10548

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14167 AN: 67976

Other (OTH) AF: 0.345 AC: 728 AN: 2108

Alfa AF: 0.251 Hom.: 6475

Bravo AF: 0.324

Asia WGS AF: 0.432 AC: 1498 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.8
DANN	Benign	0.29
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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: rs12435797; hg19: chr14-73797669;