rs520803

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004557.4(NOTCH4):​c.852G>T​(p.Gln284His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. Q284Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NOTCH4
NM_004557.4 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14540023).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.852G>T p.Gln284His missense_variant 5/30 ENST00000375023.3
NOTCH4NR_134949.2 linkuse as main transcriptn.991G>T non_coding_transcript_exon_variant 5/30
NOTCH4NR_134950.2 linkuse as main transcriptn.991G>T 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>T p.Gln284His missense_variant 5/301 NM_004557.4 P1Q99466-1
NOTCH4ENST00000473562.1 linkuse as main transcriptn.981G>T non_coding_transcript_exon_variant 5/111

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1461862
Hom.:
0
Cov.:
52
AF XY:
0.00
AC XY:
0
AN XY:
727240
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
0.21
DANN
Benign
0.86
DEOGEN2
Uncertain
0.42
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.030
N
LIST_S2
Benign
0.35
T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.23
Sift
Benign
0.13
T
Sift4G
Uncertain
0.019
D
Polyphen
0.0040
B
Vest4
0.14
MutPred
0.47
Gain of catalytic residue at Q284 (P = 0.0238);
MVP
0.58
MPC
0.17
ClinPred
0.063
T
GERP RS
-5.3
Varity_R
0.062
gMVP
0.78

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; API