14-73410218-G-C

Variant names:

• chr14-73410218-G-C
• rs2108552
• NM_001005743.2:c.-232-150C>G

Variant summary

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

The NM_001005743.2(NUMB):​c.-232-150C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,098 control chromosomes in the GnomAD database, including 3,401 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 0.18 (3401 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NUMB NM_001005743.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.-232-150C>G		intron_variant	Intron 1 of 12	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.-232-150C>G		intron_variant	Intron 1 of 12	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28092 AN: 151980 Hom.: 3399 Cov.: 32

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.201

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.500 AC: 1 AN: 2 Hom.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.185 AC: 28097 AN: 152098 Hom.: 3401 Cov.: 32 AF XY: 0.195 AC XY: 14515 AN XY: 74362

African (AFR) AF: 0.0844 AC: 3498 AN: 41432

American (AMR) AF: 0.310 AC: 4731 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1043 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2810 AN: 5180

South Asian (SAS) AF: 0.245 AC: 1186 AN: 4834

European-Finnish (FIN) AF: 0.239 AC: 2527 AN: 10576

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11641 AN: 68022

Other (OTH) AF: 0.199 AC: 419 AN: 2110

Alfa AF: 0.0847 Hom.: 164

Bravo AF: 0.184

Asia WGS AF: 0.309 AC: 1075 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.75
PhyloP100		0.084
PromoterAI		0.0076	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2108552; hg19: chr14-73876926;