rs35887416

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000263388.7(NOTCH3):​c.5370C>T​(p.Phe1790=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,614,090 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 5 hom. )

Consequence

NOTCH3
ENST00000263388.7 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.94
Variant links:
Genes affected
NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 19-15166084-G-A is Benign according to our data. Variant chr19-15166084-G-A is described in ClinVar as [Benign]. Clinvar id is 256142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00261 (398/152308) while in subpopulation AFR AF= 0.00893 (371/41564). AF 95% confidence interval is 0.00818. There are 1 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 398 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH3NM_000435.3 linkuse as main transcriptc.5370C>T p.Phe1790= synonymous_variant 30/33 ENST00000263388.7 NP_000426.2
NOTCH3XM_005259924.5 linkuse as main transcriptc.5214C>T p.Phe1738= synonymous_variant 29/32 XP_005259981.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH3ENST00000263388.7 linkuse as main transcriptc.5370C>T p.Phe1790= synonymous_variant 30/331 NM_000435.3 ENSP00000263388 P1
NOTCH3ENST00000595514.1 linkuse as main transcriptc.229-569C>T intron_variant, NMD_transcript_variant 3 ENSP00000470661

Frequencies

GnomAD3 genomes
AF:
0.00262
AC:
399
AN:
152190
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00898
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.000575
AC:
144
AN:
250532
Hom.:
0
AF XY:
0.000384
AC XY:
52
AN XY:
135500
show subpopulations
Gnomad AFR exome
AF:
0.00794
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000267
AC:
390
AN:
1461782
Hom.:
5
Cov.:
34
AF XY:
0.000237
AC XY:
172
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00962
Gnomad4 AMR exome
AF:
0.000402
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.000530
GnomAD4 genome
AF:
0.00261
AC:
398
AN:
152308
Hom.:
1
Cov.:
32
AF XY:
0.00254
AC XY:
189
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00893
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00110
Hom.:
0
Bravo
AF:
0.00270
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2023- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022NOTCH3: BS1, BS2 -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 21, 2017- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.43
CADD
Benign
8.7
DANN
Benign
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs35887416; hg19: chr19-15276895; API