NM_001005743.2:c.1875T>C

Variant names:

• chr14-73276659-A-G
• rs177381
• NM_001005743.2:c.1875T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001005743.2(NUMB):​c.1875T>C​(p.Asn625Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,614,052 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (85 hom.)
• Consequence: NUMB NM_001005743.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.12
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-73276659-A-G is Benign according to our data. Variant chr14-73276659-A-G is described in ClinVar as [Benign]. Clinvar id is 769401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0149 (2269/152168) while in subpopulation AFR AF = 0.039 (1618/41530). AF 95% confidence interval is 0.0374. There are 39 homozygotes in GnomAd4. There are 1083 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.1875T>C	p.Asn625Asn	synonymous_variant	Exon 13 of 13	ENST00000555238.6	NP_001005743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUMB	ENST00000555238.6	c.1875T>C	p.Asn625Asn	synonymous_variant	Exon 13 of 13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2265 AN: 152050 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.00689 AC: 1734 AN: 251490 AF XY: 0.00584

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00403 AC: 5896 AN: 1461884 Hom.: 85 Cov.: 31 AF XY: 0.00393 AC XY: 2858 AN XY: 727240

African (AFR) AF: 0.0406 AC: 1360 AN: 33480

American (AMR) AF: 0.0130 AC: 583 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 606 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86256

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53420

Middle Eastern (MID) AF: 0.0239 AC: 138 AN: 5768

European-Non Finnish (NFE) AF: 0.00227 AC: 2526 AN: 1112004

Other (OTH) AF: 0.0107 AC: 649 AN: 60396

GnomAD4 genome AF: 0.0149 AC: 2269 AN: 152168 Hom.: 39 Cov.: 32 AF XY: 0.0146 AC XY: 1083 AN XY: 74400

African (AFR) AF: 0.0390 AC: 1618 AN: 41530

American (AMR) AF: 0.0205 AC: 314 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10574

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00275 AC: 187 AN: 67990

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0124 Hom.: 29

Bravo AF: 0.0183

EpiCase AF: 0.00583

EpiControl AF: 0.00486

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.7
DANN	Benign	0.80
PhyloP100		3.1
Mutation Taster		=99/1	polymorphism

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: rs177381; hg19: chr14-73743367;