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GeneBe

14-73276596-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001005743.2(NUMB):c.1938G>A(p.Thr646=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,612,212 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0020 ( 6 hom. )

Consequence

NUMB
NM_001005743.2 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.78
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 -11 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=-0.66).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-73276596-C-T is Benign according to our data. Variant chr14-73276596-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2644361.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=-2.78 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 236 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NUMBNM_001005743.2 linkuse as main transcriptc.1938G>A p.Thr646= synonymous_variant 13/13 ENST00000555238.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NUMBENST00000555238.6 linkuse as main transcriptc.1938G>A p.Thr646= synonymous_variant 13/131 NM_001005743.2 P4P49757-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00155
AC:
236
AN:
152174
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00720
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00256
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00167
AC:
418
AN:
250684
Hom.:
0
AF XY:
0.00171
AC XY:
231
AN XY:
135474
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.00851
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000623
Gnomad FIN exome
AF:
0.00139
Gnomad NFE exome
AF:
0.00224
Gnomad OTH exome
AF:
0.00262
GnomAD4 exome
AF:
0.00204
AC:
2978
AN:
1459920
Hom.:
6
Cov.:
31
AF XY:
0.00207
AC XY:
1504
AN XY:
725964
show subpopulations
Gnomad4 AFR exome
AF:
0.000479
Gnomad4 AMR exome
AF:
0.000269
Gnomad4 ASJ exome
AF:
0.00867
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.000801
Gnomad4 FIN exome
AF:
0.000937
Gnomad4 NFE exome
AF:
0.00226
Gnomad4 OTH exome
AF:
0.00144
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00155
AC:
236
AN:
152292
Hom.:
1
Cov.:
32
AF XY:
0.00136
AC XY:
101
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00720
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00256
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00235
Hom.:
1
Bravo
AF:
0.00145
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00224
EpiControl
AF:
0.00178

ClinVar

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

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022NUMB: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.66
Cadd
Benign
0.11
Dann
Benign
0.79

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: rs117957039; hg19: chr14-73743304; COSMIC: COSV53714668; COSMIC: COSV53714668; API