6-32195940-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004557.4(NOTCH4):​c.5509G>A​(p.Ala1837Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000798 in 1,590,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011393398).
BS2
High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH4NM_004557.4 linkuse as main transcriptc.5509G>A p.Ala1837Thr missense_variant 30/30 ENST00000375023.3 NP_004548.3 Q99466-1A0A1U9X983
NOTCH4NR_134949.2 linkuse as main transcriptn.5217G>A non_coding_transcript_exon_variant 30/30
NOTCH4NR_134950.2 linkuse as main transcriptn.5115G>A non_coding_transcript_exon_variant 29/29

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH4ENST00000375023.3 linkuse as main transcriptc.5509G>A p.Ala1837Thr missense_variant 30/301 NM_004557.4 ENSP00000364163.3 Q99466-1
NOTCH4ENST00000474612.1 linkuse as main transcriptn.4170G>A non_coding_transcript_exon_variant 10/105
NOTCH4ENST00000491215.1 linkuse as main transcriptn.535G>A non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000116
AC:
24
AN:
207448
Hom.:
0
AF XY:
0.000121
AC XY:
14
AN XY:
115800
show subpopulations
Gnomad AFR exome
AF:
0.00134
Gnomad AMR exome
AF:
0.000184
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:
0.0000216
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000563
AC:
81
AN:
1438394
Hom.:
0
Cov.:
32
AF XY:
0.0000531
AC XY:
38
AN XY:
715268
show subpopulations
Gnomad4 AFR exome
AF:
0.000932
Gnomad4 AMR exome
AF:
0.000184
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:
0.0000298
Gnomad4 OTH exome
AF:
0.000151
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.000376
AC XY:
28
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00104
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000238
Hom.:
0
Bravo
AF:
0.000280
ExAC
AF:
0.000104
AC:
12

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 GeneticsSep 18, 2024The c.5509G>A (p.A1837T) 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 5509, causing the alanine (A) at amino acid position 1837 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
0.094
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
6.4
DANN
Benign
0.95
DEOGEN2
Benign
0.028
T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.048
N
LIST_S2
Benign
0.63
T
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.49
N
REVEL
Benign
0.098
Sift
Benign
0.21
T
Sift4G
Benign
0.062
T
Polyphen
0.0040
B
Vest4
0.10
MVP
0.59
MPC
0.60
ClinPred
0.020
T
GERP RS
0.71
Varity_R
0.019
gMVP
0.34

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: rs200319129; hg19: chr6-32163717; API