rs78857347

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_017617.5(NOTCH1):​c.4290C>T​(p.Tyr1430=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,611,646 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.752
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 9-136505606-G-A is Benign according to our data. Variant chr9-136505606-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136505606-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.752 with no splicing effect.
BS2
High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.4290C>T p.Tyr1430= synonymous_variant 25/34 ENST00000651671.1 NP_060087.3
NOTCH1XM_011518717.3 linkuse as main transcriptc.3567C>T p.Tyr1189= synonymous_variant 22/31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.4290C>T p.Tyr1430= synonymous_variant 25/34 NM_017617.5 ENSP00000498587 P1

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000323
AC:
79
AN:
244820
Hom.:
0
AF XY:
0.000306
AC XY:
41
AN XY:
133870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00426
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000906
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.000147
AC:
214
AN:
1459288
Hom.:
2
Cov.:
33
AF XY:
0.000145
AC XY:
105
AN XY:
725848
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00509
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152358
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00367
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.000102
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 11, 2024- -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 10, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Adams-Oliver syndrome 5 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
CADD
Benign
4.7
DANN
Benign
0.91
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs78857347; hg19: chr9-139400058; API