rs8192585

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004557.4(NOTCH4):​c.731C>T​(p.Ser244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,611,614 control chromosomes in the GnomAD database, including 1,522 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.035 ( 117 hom., cov: 33)
Exomes 𝑓: 0.042 ( 1405 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

18

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.69
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0051605105).
BP6
Variant 6-32221046-G-A is Benign according to our data. Variant chr6-32221046-G-A is described in ClinVar as [Benign]. Clinvar id is 1232512.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0349 (5320/152280) while in subpopulation NFE AF= 0.0456 (3099/67990). AF 95% confidence interval is 0.0442. There are 117 homozygotes in gnomad4. There are 2640 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 5320 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.731C>T p.Ser244Leu missense_variant 4/30 ENST00000375023.3
NOTCH4NR_134949.2 linkuse as main transcriptn.870C>T non_coding_transcript_exon_variant 4/30
NOTCH4NR_134950.2 linkuse as main transcriptn.870C>T non_coding_transcript_exon_variant 4/29

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH4ENST00000375023.3 linkuse as main transcriptc.731C>T p.Ser244Leu missense_variant 4/301 NM_004557.4 P1Q99466-1
NOTCH4ENST00000473562.1 linkuse as main transcriptn.860C>T non_coding_transcript_exon_variant 4/111

Frequencies

GnomAD3 genomes
AF:
0.0349
AC:
5312
AN:
152162
Hom.:
116
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0208
Gnomad AMI
AF:
0.0132
Gnomad AMR
AF:
0.0285
Gnomad ASJ
AF:
0.00894
Gnomad EAS
AF:
0.0168
Gnomad SAS
AF:
0.0290
Gnomad FIN
AF:
0.0547
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0456
Gnomad OTH
AF:
0.0287
GnomAD3 exomes
AF:
0.0357
AC:
8771
AN:
245824
Hom.:
198
AF XY:
0.0356
AC XY:
4770
AN XY:
133854
show subpopulations
Gnomad AFR exome
AF:
0.0187
Gnomad AMR exome
AF:
0.0283
Gnomad ASJ exome
AF:
0.00924
Gnomad EAS exome
AF:
0.0179
Gnomad SAS exome
AF:
0.0294
Gnomad FIN exome
AF:
0.0554
Gnomad NFE exome
AF:
0.0438
Gnomad OTH exome
AF:
0.0311
GnomAD4 exome
AF:
0.0417
AC:
60837
AN:
1459334
Hom.:
1405
Cov.:
55
AF XY:
0.0415
AC XY:
30155
AN XY:
725760
show subpopulations
Gnomad4 AFR exome
AF:
0.0189
Gnomad4 AMR exome
AF:
0.0278
Gnomad4 ASJ exome
AF:
0.00961
Gnomad4 EAS exome
AF:
0.0308
Gnomad4 SAS exome
AF:
0.0300
Gnomad4 FIN exome
AF:
0.0568
Gnomad4 NFE exome
AF:
0.0448
Gnomad4 OTH exome
AF:
0.0335
GnomAD4 genome
AF:
0.0349
AC:
5320
AN:
152280
Hom.:
117
Cov.:
33
AF XY:
0.0355
AC XY:
2640
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0208
Gnomad4 AMR
AF:
0.0288
Gnomad4 ASJ
AF:
0.00894
Gnomad4 EAS
AF:
0.0168
Gnomad4 SAS
AF:
0.0288
Gnomad4 FIN
AF:
0.0547
Gnomad4 NFE
AF:
0.0456
Gnomad4 OTH
AF:
0.0284
Alfa
AF:
0.0389
Hom.:
272
Bravo
AF:
0.0308
TwinsUK
AF:
0.0515
AC:
191
ALSPAC
AF:
0.0407
AC:
157
ESP6500AA
AF:
0.0172
AC:
52
ESP6500EA
AF:
0.0382
AC:
207
ExAC
AF:
0.0351
AC:
4217
Asia WGS
AF:
0.0250
AC:
86
AN:
3476
EpiCase
AF:
0.0415
EpiControl
AF:
0.0420

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, 2021This variant is associated with the following publications: (PMID: 19197363) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
0.011
DANN
Benign
0.54
DEOGEN2
Benign
0.18
T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.16
T
MetaRNN
Benign
0.0052
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-1.8
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.91
N
REVEL
Benign
0.22
Sift
Benign
0.68
T
Sift4G
Benign
1.0
T
Polyphen
0.0020
B
Vest4
0.044
MPC
0.16
ClinPred
0.011
T
GERP RS
-6.9
Varity_R
0.036
gMVP
0.32

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: rs8192585; hg19: chr6-32188823; COSMIC: COSV66681518; API