6-32196044-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004557.4(NOTCH4):c.5405C>A(p.Ala1802Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,594,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12

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]

NOTCH4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10237098).

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.5405C>A	p.Ala1802Glu	missense_variant	Exon 30 of 30	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.5113C>A		non_coding_transcript_exon_variant	Exon 30 of 30
NOTCH4	NR_134950.2 link	n.5011C>A		non_coding_transcript_exon_variant	Exon 29 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOTCH4	ENST00000375023.3 link	c.5405C>A	p.Ala1802Glu	missense_variant	Exon 30 of 30	1	NM_004557.4	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000474612.1 link	n.4066C>A		non_coding_transcript_exon_variant	Exon 10 of 10	5
NOTCH4	ENST00000491215.1 link	n.431C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000807

AC:

AN:

210680

Hom.:

AF XY:

0.0000851

AC XY:

AN XY:

117548

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.0000305

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:

0.0000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000374

AC:

AN:

1442024

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

717484

show subpopulations

Gnomad4 AFR exome

AF:

0.000781

Gnomad4 AMR exome

AF:

0.0000228

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:

0.0000225

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.000184

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000603

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.000242

ExAC

AF:

0.0000344

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5405C>A (p.A1802E) alteration is located in exon 30 (coding exon 30) of the NOTCH4 gene. This alteration results from a C to A substitution at nucleotide position 5405, causing the alanine (A) at amino acid position 1802 to be replaced by a glutamic acid (E). 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

0.18

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.11

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.31

Sift

Uncertain

0.016

Sift4G

Benign

0.088

Polyphen

0.17

Vest4

0.41

MVP

0.93

MPC

1.1

ClinPred

0.16

GERP RS

2.8

Varity_R

0.15

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over