rs2229970

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017617.5(NOTCH1):​c.2205C>T​(p.Asn735=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,577,522 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 61 hom., cov: 33)
Exomes 𝑓: 0.0017 ( 58 hom. )

Consequence

NOTCH1
NM_017617.5 splice_region, synonymous

Scores

2
Splicing: ADA: 0.006260
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.419
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
Variant 9-136514512-G-A is Benign according to our data. Variant chr9-136514512-G-A is described in ClinVar as [Benign]. Clinvar id is 241122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136514512-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.419 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.2205C>T p.Asn735= splice_region_variant, synonymous_variant 13/34 ENST00000651671.1 NP_060087.3
LOC124902310XR_007061865.1 linkuse as main transcriptn.507+4533G>A intron_variant, non_coding_transcript_variant
NOTCH1XM_011518717.3 linkuse as main transcriptc.1482C>T p.Asn494= splice_region_variant, synonymous_variant 10/31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.2205C>T p.Asn735= splice_region_variant, synonymous_variant 13/34 NM_017617.5 ENSP00000498587 P1

Frequencies

GnomAD3 genomes
AF:
0.0161
AC:
2449
AN:
152212
Hom.:
61
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0561
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00562
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00908
GnomAD3 exomes
AF:
0.00413
AC:
790
AN:
191448
Hom.:
21
AF XY:
0.00308
AC XY:
318
AN XY:
103388
show subpopulations
Gnomad AFR exome
AF:
0.0611
Gnomad AMR exome
AF:
0.00211
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00102
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000109
Gnomad OTH exome
AF:
0.000204
GnomAD4 exome
AF:
0.00174
AC:
2476
AN:
1425192
Hom.:
58
Cov.:
33
AF XY:
0.00148
AC XY:
1046
AN XY:
705772
show subpopulations
Gnomad4 AFR exome
AF:
0.0600
Gnomad4 AMR exome
AF:
0.00250
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000130
Gnomad4 SAS exome
AF:
0.000991
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000539
Gnomad4 OTH exome
AF:
0.00382
GnomAD4 genome
AF:
0.0162
AC:
2461
AN:
152330
Hom.:
61
Cov.:
33
AF XY:
0.0155
AC XY:
1154
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0562
Gnomad4 AMR
AF:
0.00555
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00899
Alfa
AF:
0.00852
Hom.:
16
Bravo
AF:
0.0179
Asia WGS
AF:
0.00693
AC:
24
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxSep 28, 2016This 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. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 28, 2023- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 16, 2023- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Adams-Oliver syndrome 5 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2015This alteration is classified as 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. -
Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 05, 2022- -
Aortic valve disease 1 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.47
CADD
Benign
0.27
DANN
Benign
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0063
dbscSNV1_RF
Benign
0.16
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: rs2229970; hg19: chr9-139408964; COSMIC: COSV53044579; COSMIC: COSV53044579; API