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GeneBe

6-32195985-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004557.4(NOTCH4):c.5464G>A(p.Ala1822Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,598,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.801
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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13144448).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.5464G>A p.Ala1822Thr missense_variant 30/30 ENST00000375023.3
NOTCH4NR_134949.2 linkuse as main transcriptn.5172G>A non_coding_transcript_exon_variant 30/30
NOTCH4NR_134950.2 linkuse as main transcriptn.5070G>A 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.5464G>A p.Ala1822Thr missense_variant 30/301 NM_004557.4 P1Q99466-1
NOTCH4ENST00000474612.1 linkuse as main transcriptn.4125G>A non_coding_transcript_exon_variant 10/105
NOTCH4ENST00000491215.1 linkuse as main transcriptn.490G>A non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152260
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000136
AC:
3
AN:
220718
Hom.:
0
AF XY:
0.00000814
AC XY:
1
AN XY:
122822
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000888
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000346
AC:
5
AN:
1446290
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
719868
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000449
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000250
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152260
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.00000859
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 07, 2022The c.5464G>A (p.A1822T) alteration is located in exon 30 (coding exon 30) of the NOTCH4 gene. This alteration results from a G to A substitution at nucleotide position 5464, causing the alanine (A) at amino acid position 1822 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Benign
-0.15
Cadd
Benign
19
Dann
Uncertain
1.0
DEOGEN2
Benign
0.032
T
Eigen
Benign
0.076
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.59
T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.35
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
0.51
D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.46
N
REVEL
Benign
0.24
Sift
Benign
0.24
T
Sift4G
Benign
0.26
T
Polyphen
0.35
B
Vest4
0.083
MutPred
0.21
Gain of glycosylation at A1822 (P = 0.0155);
MVP
0.88
MPC
0.60
ClinPred
0.54
D
GERP RS
5.0
Varity_R
0.035
gMVP
0.28

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: rs766900262; hg19: chr6-32163762; API