chr6-32196022-T-C

Variant summary

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

The NM_004557.4(NOTCH4):ā€‹c.5427A>Gā€‹(p.Gln1809=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,598,326 control chromosomes in the GnomAD database, including 2,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…).

Frequency

Genomes: š‘“ 0.062 ( 343 hom., cov: 33)
Exomes š‘“: 0.056 ( 2542 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.165
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=-0.61).
BP6
Variant 6-32196022-T-C is Benign according to our data. Variant chr6-32196022-T-C is described in ClinVar as [Benign]. Clinvar id is 1290716.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.165 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0916 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.5427A>G p.Gln1809= synonymous_variant 30/30 ENST00000375023.3
NOTCH4NR_134949.2 linkuse as main transcriptn.5135A>G non_coding_transcript_exon_variant 30/30
NOTCH4NR_134950.2 linkuse as main transcriptn.5033A>G non_coding_transcript_exon_variant 29/29

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH4ENST00000375023.3 linkuse as main transcriptc.5427A>G p.Gln1809= synonymous_variant 30/301 NM_004557.4 P1Q99466-1
NOTCH4ENST00000474612.1 linkuse as main transcriptn.4088A>G non_coding_transcript_exon_variant 10/105
NOTCH4ENST00000491215.1 linkuse as main transcriptn.453A>G non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
AF:
0.0616
AC:
9371
AN:
152118
Hom.:
345
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0814
Gnomad AMI
AF:
0.156
Gnomad AMR
AF:
0.0506
Gnomad ASJ
AF:
0.0456
Gnomad EAS
AF:
0.0465
Gnomad SAS
AF:
0.0993
Gnomad FIN
AF:
0.0183
Gnomad MID
AF:
0.0696
Gnomad NFE
AF:
0.0566
Gnomad OTH
AF:
0.0669
GnomAD3 exomes
AF:
0.0531
AC:
11572
AN:
217950
Hom.:
409
AF XY:
0.0569
AC XY:
6906
AN XY:
121402
show subpopulations
Gnomad AFR exome
AF:
0.0810
Gnomad AMR exome
AF:
0.0313
Gnomad ASJ exome
AF:
0.0466
Gnomad EAS exome
AF:
0.0365
Gnomad SAS exome
AF:
0.0971
Gnomad FIN exome
AF:
0.0169
Gnomad NFE exome
AF:
0.0516
Gnomad OTH exome
AF:
0.0557
GnomAD4 exome
AF:
0.0562
AC:
81251
AN:
1446090
Hom.:
2542
Cov.:
32
AF XY:
0.0571
AC XY:
41073
AN XY:
719706
show subpopulations
Gnomad4 AFR exome
AF:
0.0893
Gnomad4 AMR exome
AF:
0.0346
Gnomad4 ASJ exome
AF:
0.0496
Gnomad4 EAS exome
AF:
0.0539
Gnomad4 SAS exome
AF:
0.0934
Gnomad4 FIN exome
AF:
0.0212
Gnomad4 NFE exome
AF:
0.0544
Gnomad4 OTH exome
AF:
0.0593
GnomAD4 genome
AF:
0.0615
AC:
9369
AN:
152236
Hom.:
343
Cov.:
33
AF XY:
0.0604
AC XY:
4499
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0812
Gnomad4 AMR
AF:
0.0505
Gnomad4 ASJ
AF:
0.0456
Gnomad4 EAS
AF:
0.0468
Gnomad4 SAS
AF:
0.0989
Gnomad4 FIN
AF:
0.0183
Gnomad4 NFE
AF:
0.0566
Gnomad4 OTH
AF:
0.0662
Alfa
AF:
0.0424
Hom.:
56
Bravo
AF:
0.0648
Asia WGS
AF:
0.0690
AC:
240
AN:
3478

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 05, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.61
CADD
Benign
9.1
DANN
Benign
0.85

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: rs8192579; hg19: chr6-32163799; COSMIC: COSV66678923; COSMIC: COSV66678923; API