rs8192591

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_004557.4(NOTCH4):c.1600G>A(p.Gly534Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 1,613,200 control chromosomes in the GnomAD database, including 1,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1027 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0710

Publications

58 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004939854).

BP6

Variant 6-32218019-C-T is Benign according to our data. Variant chr6-32218019-C-T is described in ClinVar as Benign. ClinVar VariationId is 1220553.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

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.1600G>A	p.Gly534Ser	missense	Exon 9 of 30	NP_004548.3
NOTCH4	NR_134949.2		n.1841G>A		non_coding_transcript_exon	Exon 10 of 30
NOTCH4	NR_134950.2		n.1739G>A		non_coding_transcript_exon	Exon 9 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.1600G>A	p.Gly534Ser	missense	Exon 9 of 30	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000473562.1	TSL:1	n.1729G>A		non_coding_transcript_exon	Exon 9 of 11
NOTCH4	ENST00000883244.1		c.1600G>A	p.Gly534Ser	missense	Exon 9 of 30	ENSP00000553303.1

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3398

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00522

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.00931

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00984

Gnomad SAS

AF:

0.0585

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.0248

AC:

6220

AN:

250774

AF XY:

0.0273

show subpopulations

Gnomad AFR exome

AF:

0.00580

Gnomad AMR exome

AF:

0.00637

Gnomad ASJ exome

AF:

0.00497

Gnomad EAS exome

AF:

0.00484

Gnomad FIN exome

AF:

0.00976

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.0336

AC:

49116

AN:

1461036

Hom.:

1027

Cov.:

AF XY:

0.0339

AC XY:

24641

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.00583

AC:

195

AN:

33466

American (AMR)

AF:

0.00691

AC:

309

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00505

AC:

132

AN:

26136

East Asian (EAS)

AF:

0.00363

AC:

144

AN:

39698

South Asian (SAS)

AF:

0.0512

AC:

4409

AN:

86180

European-Finnish (FIN)

AF:

0.0121

AC:

646

AN:

53384

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0372

AC:

41375

AN:

1111328

Other (OTH)

AF:

0.0302

AC:

1823

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2263

4526

6789

9052

11315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1572

3144

4716

6288

7860

<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:

0.0223

AC:

3395

AN:

152164

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1592

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00520

AC:

216

AN:

41508

American (AMR)

AF:

0.00929

AC:

142

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00986

AC:

AN:

5170

South Asian (SAS)

AF:

0.0579

AC:

279

AN:

4818

European-Finnish (FIN)

AF:

0.0103

AC:

109

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0351

AC:

2387

AN:

68000

Other (OTH)

AF:

0.0190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

173

346

520

693

866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0296

Hom.:

326

Bravo

AF:

0.0211

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0360

AC:

310

ExAC

AF:

0.0263

AC:

3194

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0359

EpiControl

AF:

0.0340

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.3

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.043

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.17

PhyloP100

0.071

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

REVEL

Benign

0.27

Sift

Benign

0.040

Sift4G

Benign

0.18

Polyphen

0.85

Vest4

0.055

MPC

0.38

ClinPred

0.022

GERP RS

2.4

Varity_R

0.050

gMVP

0.64

Mutation Taster

=97/3

polymorphism (auto)

(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