rs520692

Variant names:

Variant summary

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

The NM_004557.4(NOTCH4):c.815A>G(p.Asp272Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,300 control chromosomes in the GnomAD database, including 76,302 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.29 ( 6808 hom., cov: 33)

Exomes 𝑓: 0.30 ( 69494 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.64

Publications

53 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=0.013173163).

BP6

Variant 6-32220863-T-C is Benign according to our data. Variant chr6-32220863-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287249.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.815A>G	p.Asp272Gly	missense_variant	Exon 5 of 30	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.954A>G		non_coding_transcript_exon_variant	Exon 5 of 30
NOTCH4	NR_134950.2 link	n.954A>G		non_coding_transcript_exon_variant	Exon 5 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.815A>G	p.Asp272Gly	missense_variant	Exon 5 of 30	1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000473562.1 link	n.944A>G		non_coding_transcript_exon_variant	Exon 5 of 11	1

Frequencies

GnomAD3 genomes

AF:

0.290

AC:

44094

AN:

151888

Hom.:

6807

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.396

Gnomad AMR

AF:

0.322

Gnomad ASJ

AF:

0.506

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.316

Gnomad FIN

AF:

0.313

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.313

GnomAD2 exomes

AF:

0.305

AC:

76557

AN:

250830

AF XY:

0.315

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.313

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.333

GnomAD4 exome

AF:

0.302

AC:

441941

AN:

1461296

Hom.:

69494

Cov.:

AF XY:

0.306

AC XY:

222448

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.217

AC:

7280

AN:

33474

American (AMR)

AF:

0.269

AC:

12003

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.501

AC:

13057

AN:

26064

East Asian (EAS)

AF:

0.190

AC:

7549

AN:

39692

South Asian (SAS)

AF:

0.330

AC:

28434

AN:

86180

European-Finnish (FIN)

AF:

0.308

AC:

16456

AN:

53388

Middle Eastern (MID)

AF:

0.396

AC:

2284

AN:

5766

European-Non Finnish (NFE)

AF:

0.302

AC:

336144

AN:

1111692

Other (OTH)

AF:

0.310

AC:

18734

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

18826

37653

56479

75306

94132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10728

21456

32184

42912

53640

<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:

0.290

AC:

44094

AN:

152004

Hom.:

6808

Cov.:

AF XY:

0.291

AC XY:

21612

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.211

AC:

8758

AN:

41492

American (AMR)

AF:

0.322

AC:

4918

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

1752

AN:

3464

East Asian (EAS)

AF:

0.164

AC:

846

AN:

5162

South Asian (SAS)

AF:

0.316

AC:

1524

AN:

4826

European-Finnish (FIN)

AF:

0.313

AC:

3315

AN:

10580

Middle Eastern (MID)

AF:

0.418

AC:

122

AN:

292

European-Non Finnish (NFE)

AF:

0.322

AC:

21836

AN:

67884

Other (OTH)

AF:

0.315

AC:

664

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1632

3264

4896

6528

8160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.317

Hom.:

19599

Bravo

AF:

0.286

TwinsUK

AF:

0.283

AC:

1050

ALSPAC

AF:

0.282

AC:

1085

ESP6500AA

AF:

0.213

AC:

937

ESP6500EA

AF:

0.319

AC:

2742

ExAC

AF:

0.305

AC:

37080

Asia WGS

AF:

0.321

AC:

1122

AN:

3478

EpiCase

AF:

0.350

EpiControl

AF:

0.361

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.37

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.48

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.9

PhyloP100

1.6

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Benign

0.34

Sift4G

Benign

0.53

Polyphen

0.0010

Vest4

0.037

MPC

0.24

ClinPred

0.0069

GERP RS

3.6

Varity_R

0.15

gMVP

0.66

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over