rs200319129

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1837V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011393398).

BS2

High AC in GnomAd4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004557.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOTCH4	NM_004557.4	MANE Select	c.5509G>A	p.Ala1837Thr	missense	Exon 30 of 30	NP_004548.3
NOTCH4	NR_134949.2		n.5217G>A		non_coding_transcript_exon	Exon 30 of 30
NOTCH4	NR_134950.2		n.5115G>A		non_coding_transcript_exon	Exon 29 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.5509G>A	p.Ala1837Thr	missense	Exon 30 of 30	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000883244.1		c.5500G>A	p.Ala1834Thr	missense	Exon 30 of 30	ENSP00000553303.1
NOTCH4	ENST00000883245.1		c.5377G>A	p.Ala1793Thr	missense	Exon 29 of 29	ENSP00000553304.1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152248

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000116

AC:

AN:

207448

AF XY:

0.000121

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000216

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000563

AC:

AN:

1438394

Hom.:

Cov.:

AF XY:

0.0000531

AC XY:

AN XY:

715268

show subpopulations

African (AFR)

AF:

0.000932

AC:

AN:

33250

American (AMR)

AF:

0.000184

AC:

AN:

43580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25812

East Asian (EAS)

AF:

0.00

AC:

AN:

39320

South Asian (SAS)

AF:

0.00

AC:

AN:

85048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

1107722

Other (OTH)

AF:

0.000151

AC:

AN:

59784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41472

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000202

Hom.:

Bravo

AF:

0.000280

ExAC

AF:

0.000104

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.30

CADD

Benign

6.4

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.028

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.63

M_CAP

Benign

0.056

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.49

REVEL

Benign

0.098

Sift

Benign

0.21

Sift4G

Benign

0.062

Polyphen

0.0040

Vest4

0.10

MVP

0.59

MPC

0.60

ClinPred

0.020

GERP RS

0.71

PromoterAI

0.10

Neutral

(source)

Varity_R

0.019

gMVP

0.34

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over