6-32220826-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_004557.4(NOTCH4):​c.852G>A​(p.Gln284=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,788 control chromosomes in the GnomAD database, including 76,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.29 ( 6864 hom., cov: 33)
Exomes 𝑓: 0.30 ( 69551 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.33
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 6-32220826-C-T is Benign according to our data. Variant chr6-32220826-C-T is described in ClinVar as [Benign]. Clinvar id is 1279259.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-3.33 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.852G>A p.Gln284= synonymous_variant 5/30 ENST00000375023.3
NOTCH4NR_134949.2 linkuse as main transcriptn.991G>A non_coding_transcript_exon_variant 5/30
NOTCH4NR_134950.2 linkuse as main transcriptn.991G>A non_coding_transcript_exon_variant 5/29

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH4ENST00000375023.3 linkuse as main transcriptc.852G>A p.Gln284= synonymous_variant 5/301 NM_004557.4 P1Q99466-1
NOTCH4ENST00000473562.1 linkuse as main transcriptn.981G>A non_coding_transcript_exon_variant 5/111

Frequencies

GnomAD3 genomes
AF:
0.291
AC:
44182
AN:
151982
Hom.:
6862
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.212
Gnomad AMI
AF:
0.398
Gnomad AMR
AF:
0.323
Gnomad ASJ
AF:
0.507
Gnomad EAS
AF:
0.164
Gnomad SAS
AF:
0.316
Gnomad FIN
AF:
0.314
Gnomad MID
AF:
0.415
Gnomad NFE
AF:
0.322
Gnomad OTH
AF:
0.313
GnomAD3 exomes
AF:
0.306
AC:
76887
AN:
251330
Hom.:
12826
AF XY:
0.315
AC XY:
42828
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.210
Gnomad AMR exome
AF:
0.265
Gnomad ASJ exome
AF:
0.508
Gnomad EAS exome
AF:
0.136
Gnomad SAS exome
AF:
0.334
Gnomad FIN exome
AF:
0.314
Gnomad NFE exome
AF:
0.331
Gnomad OTH exome
AF:
0.334
GnomAD4 exome
AF:
0.303
AC:
442177
AN:
1461688
Hom.:
69551
Cov.:
52
AF XY:
0.306
AC XY:
222572
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.218
Gnomad4 AMR exome
AF:
0.269
Gnomad4 ASJ exome
AF:
0.501
Gnomad4 EAS exome
AF:
0.190
Gnomad4 SAS exome
AF:
0.330
Gnomad4 FIN exome
AF:
0.308
Gnomad4 NFE exome
AF:
0.302
Gnomad4 OTH exome
AF:
0.311
GnomAD4 genome
AF:
0.290
AC:
44184
AN:
152100
Hom.:
6864
Cov.:
33
AF XY:
0.291
AC XY:
21654
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.211
Gnomad4 AMR
AF:
0.322
Gnomad4 ASJ
AF:
0.507
Gnomad4 EAS
AF:
0.164
Gnomad4 SAS
AF:
0.316
Gnomad4 FIN
AF:
0.314
Gnomad4 NFE
AF:
0.322
Gnomad4 OTH
AF:
0.316
Alfa
AF:
0.322
Hom.:
7392
Bravo
AF:
0.286
Asia WGS
AF:
0.321
AC:
1121
AN:
3478
EpiCase
AF:
0.350
EpiControl
AF:
0.362

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
0.67
DANN
Benign
0.40

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: rs520803; hg19: chr6-32188603; COSMIC: COSV66678390; API