9-136502993-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017617.5(NOTCH1):​c.5167+189C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00734 in 820,372 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 160 hom., cov: 33)
Exomes 𝑓: 0.0033 ( 67 hom. )

Consequence

NOTCH1
NM_017617.5 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.45
Variant links:
Genes affected
NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 9-136502993-G-T is Benign according to our data. Variant chr9-136502993-G-T is described in ClinVar as [Benign]. Clinvar id is 679857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.5167+189C>A intron_variant Intron 27 of 33 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.4444+189C>A intron_variant Intron 24 of 30 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.5167+189C>A intron_variant Intron 27 of 33 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.0251
AC:
3814
AN:
152128
Hom.:
162
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0863
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.0211
GnomAD3 exomes
AF:
0.00552
AC:
745
AN:
134916
Hom.:
31
AF XY:
0.00420
AC XY:
309
AN XY:
73496
show subpopulations
Gnomad AFR exome
AF:
0.0912
Gnomad AMR exome
AF:
0.00449
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000355
Gnomad FIN exome
AF:
0.000371
Gnomad NFE exome
AF:
0.000415
Gnomad OTH exome
AF:
0.00289
GnomAD4 exome
AF:
0.00329
AC:
2196
AN:
668126
Hom.:
67
Cov.:
9
AF XY:
0.00269
AC XY:
953
AN XY:
354234
show subpopulations
Gnomad4 AFR exome
AF:
0.0863
Gnomad4 AMR exome
AF:
0.00520
Gnomad4 ASJ exome
AF:
0.0000967
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000498
Gnomad4 FIN exome
AF:
0.000421
Gnomad4 NFE exome
AF:
0.000322
Gnomad4 OTH exome
AF:
0.00740
GnomAD4 genome
AF:
0.0251
AC:
3828
AN:
152246
Hom.:
160
Cov.:
33
AF XY:
0.0234
AC XY:
1742
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.0864
Gnomad4 AMR
AF:
0.0105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.000368
Gnomad4 OTH
AF:
0.0209
Alfa
AF:
0.00201
Hom.:
2
Bravo
AF:
0.0279
Asia WGS
AF:
0.00433
AC:
15
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 14, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
0.13
DANN
Benign
0.62

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: rs113377894; hg19: chr9-139397445; COSMIC: COSV104374550; API