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GeneBe

14-73282366-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_001005743.2(NUMB):c.1089C>T(p.Thr363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,614,086 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.030 ( 230 hom., cov: 32)
Exomes 𝑓: 0.0029 ( 191 hom. )

Consequence

NUMB
NM_001005743.2 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.72
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-73282366-G-A is Benign according to our data. Variant chr14-73282366-G-A is described in ClinVar as [Benign]. Clinvar id is 768662.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.72 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NUMBNM_001005743.2 linkuse as main transcriptc.1089C>T p.Thr363= synonymous_variant 11/13 ENST00000555238.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NUMBENST00000555238.6 linkuse as main transcriptc.1089C>T p.Thr363= synonymous_variant 11/131 NM_001005743.2 P4P49757-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0295
AC:
4496
AN:
152160
Hom.:
229
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.103
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0101
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.0210
GnomAD3 exomes
AF:
0.00779
AC:
1958
AN:
251262
Hom.:
96
AF XY:
0.00560
AC XY:
760
AN XY:
135794
show subpopulations
Gnomad AFR exome
AF:
0.105
Gnomad AMR exome
AF:
0.00544
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.00392
GnomAD4 exome
AF:
0.00293
AC:
4278
AN:
1461808
Hom.:
191
Cov.:
30
AF XY:
0.00250
AC XY:
1815
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.103
Gnomad4 AMR exome
AF:
0.00597
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000917
Gnomad4 OTH exome
AF:
0.00689
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0296
AC:
4510
AN:
152278
Hom.:
230
Cov.:
32
AF XY:
0.0284
AC XY:
2116
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.103
Gnomad4 AMR
AF:
0.0101
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.0208
Alfa
AF:
0.0190
Hom.:
59
Bravo
AF:
0.0336
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000415

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 25, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
Cadd
Benign
8.9
Dann
Benign
0.68
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61739599; hg19: chr14-73749074; API