rs3132956

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004557.4(NOTCH4):​c.2681-725C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 151,970 control chromosomes in the GnomAD database, including 965 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 965 hom., cov: 31)

Consequence

NOTCH4
NM_004557.4 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.832
Variant links:
Genes affected
NOTCH4 (HGNC:7884): (notch receptor 4) 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 may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.2681-725C>T intron_variant ENST00000375023.3
NOTCH4NR_134949.2 linkuse as main transcriptn.2922-725C>T intron_variant, non_coding_transcript_variant
NOTCH4NR_134950.2 linkuse as main transcriptn.2820-725C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH4ENST00000375023.3 linkuse as main transcriptc.2681-725C>T intron_variant 1 NM_004557.4 P1Q99466-1
NOTCH4ENST00000465528.1 linkuse as main transcriptn.554-725C>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.106
AC:
16030
AN:
151852
Hom.:
965
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0914
Gnomad AMI
AF:
0.0735
Gnomad AMR
AF:
0.0543
Gnomad ASJ
AF:
0.0767
Gnomad EAS
AF:
0.0288
Gnomad SAS
AF:
0.0948
Gnomad FIN
AF:
0.116
Gnomad MID
AF:
0.0538
Gnomad NFE
AF:
0.133
Gnomad OTH
AF:
0.0902
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.105
AC:
16027
AN:
151970
Hom.:
965
Cov.:
31
AF XY:
0.102
AC XY:
7598
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.0913
Gnomad4 AMR
AF:
0.0540
Gnomad4 ASJ
AF:
0.0767
Gnomad4 EAS
AF:
0.0291
Gnomad4 SAS
AF:
0.0940
Gnomad4 FIN
AF:
0.116
Gnomad4 NFE
AF:
0.133
Gnomad4 OTH
AF:
0.0893
Alfa
AF:
0.122
Hom.:
900
Bravo
AF:
0.101
Asia WGS
AF:
0.0540
AC:
187
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.92
CADD
Benign
5.6
DANN
Benign
0.18

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: rs3132956; hg19: chr6-32179438; API