14-73289591-A-G

Variant names:

• chr14-73289591-A-G
• rs10483853
• NM_001005743.2:c.451-2277T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005743.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMB	NM_001005743.2	MANE Select	c.451-2277T>C		intron	N/A	NP_001005743.1
	NUMB	NM_003744.6		c.418-2277T>C		intron	N/A	NP_003735.3
	NUMB	NM_001005744.2		c.451-2277T>C		intron	N/A	NP_001005744.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMB	ENST00000555238.6	TSL:1 MANE Select	c.451-2277T>C		intron	N/A	ENSP00000451300.1
	NUMB	ENST00000557597.5	TSL:1	c.418-2277T>C		intron	N/A	ENSP00000451117.1
	NUMB	ENST00000356296.8	TSL:1	c.451-2277T>C		intron	N/A	ENSP00000348644.4

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

African (AFR) AF: 0.216 AC: 8958 AN: 41496

American (AMR) AF: 0.355 AC: 5420 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1018 AN: 3464

East Asian (EAS) AF: 0.680 AC: 3516 AN: 5172

South Asian (SAS) AF: 0.239 AC: 1154 AN: 4820

European-Finnish (FIN) AF: 0.219 AC: 2325 AN: 10596

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11494 AN: 68008

Other (OTH) AF: 0.273 AC: 575 AN: 2110

Alfa AF: 0.206 Hom.: 12534

Bravo AF: 0.241

Asia WGS AF: 0.389 AC: 1351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.4
DANN	Benign	0.42
PhyloP100		1.3
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: rs10483853; hg19: chr14-73756299;