rs17781919

Variant names:

• chr14-73276750-C-T
• rs17781919
• NM_001005743.2:c.1784G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001005743.2(NUMB):​c.1784G>A​(p.Gly595Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0342 in 1,614,114 control chromosomes in the GnomAD database, including 1,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (68 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1032 hom.)
• Consequence: NUMB NM_001005743.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62
• Publications: 18 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 (MetaRNN=0.002521664).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0248 (3773/152248) while in subpopulation NFE AF = 0.0397 (2699/68012). AF 95% confidence interval is 0.0384. There are 68 homozygotes in GnomAd4. There are 1767 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3773 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUMB	NM_001005743.2	c.1784G>A	p.Gly595Asp	missense_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.1784G>A	p.Gly595Asp	missense_variant	Exon 13 of 13	1	NM_001005743.2	ENSP00000451300.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3772 AN: 152130 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0247 AC: 6208 AN: 251434 AF XY: 0.0251

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0351 AC: 51375 AN: 1461866 Hom.: 1032 Cov.: 32 AF XY: 0.0344 AC XY: 25002 AN XY: 727234

African (AFR) AF: 0.00505 AC: 169 AN: 33480

American (AMR) AF: 0.00830 AC: 371 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 540 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0121 AC: 1041 AN: 86256

European-Finnish (FIN) AF: 0.0339 AC: 1810 AN: 53414

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.0409 AC: 45434 AN: 1111994

Other (OTH) AF: 0.0322 AC: 1943 AN: 60396

GnomAD4 genome AF: 0.0248 AC: 3773 AN: 152248 Hom.: 68 Cov.: 32 AF XY: 0.0237 AC XY: 1767 AN XY: 74454

African (AFR) AF: 0.00722 AC: 300 AN: 41540

American (AMR) AF: 0.0131 AC: 201 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00685 AC: 33 AN: 4818

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2699 AN: 68012

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.0335 Hom.: 379

Bravo AF: 0.0237

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0405 AC: 348

ExAC AF: 0.0250 AC: 3040

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.45	.;.;.;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;.;.;.;D;.;.;D;D;D
MetaRNN	Benign	0.0025	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;L;.;.;.;L;.;.;.;.;.;.
PhyloP100		4.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.051	T;.;D;D;T;T;D;D;D;T;T;D;D;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.063	B;B;B;B;.;B;B;B;.;B;.;.;.;.
Vest4		0.38
MPC		0.19
ClinPred		0.0065	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.30
Mutation Taster		=97/3	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: rs17781919; hg19: chr14-73743458; COSMIC: COSV53722609; COSMIC: COSV53722609;