6-32212907-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_004557.4(NOTCH4):c.2443T>G(p.Cys815Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00436 in 1,563,840 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 29 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.55

Publications

10 publications found

Variant links:

COSMIC-nc: COSV107496120

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 -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.030241013).

BP6

Variant 6-32212907-A-C is Benign according to our data. Variant chr6-32212907-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 598 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NOTCH4	NM_004557.4 link	c.2443T>G	p.Cys815Gly	missense_variant	Exon 16 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 link	n.2684T>G		non_coding_transcript_exon_variant	Exon 17 of 30
NOTCH4	NR_134950.2 link	n.2582T>G		non_coding_transcript_exon_variant	Exon 16 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.2443T>G	p.Cys815Gly	missense_variant	Exon 16 of 30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000465528.1 link	n.399+228T>G		intron_variant	Intron 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

597

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00337

AC:

574

AN:

170274

AF XY:

0.00301

show subpopulations

Gnomad AFR exome

AF:

0.000748

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000989

Gnomad NFE exome

AF:

0.00485

Gnomad OTH exome

AF:

0.00701

GnomAD4 exome

AF:

0.00441

AC:

6224

AN:

1411618

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

2893

AN XY:

697864

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

32366

American (AMR)

AF:

0.00808

AC:

294

AN:

36388

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25084

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37112

South Asian (SAS)

AF:

0.00

AC:

AN:

80702

European-Finnish (FIN)

AF:

0.000938

AC:

AN:

50088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00519

AC:

5633

AN:

1085600

Other (OTH)

AF:

0.00374

AC:

219

AN:

58576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

284

568

853

1137

1421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.00393

AC:

598

AN:

152222

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000915

AC:

AN:

41542

American (AMR)

AF:

0.0141

AC:

215

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00473

AC:

322

AN:

68008

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

126

157

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:

0.00407

Hom.:

Bravo

AF:

0.00518

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000669

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00163

AC:

192

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Jan 01, 2013

Paul Sabatier University EA-4555, Paul Sabatier University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

MetaRNN

Benign

0.030

MetaSVM

Pathogenic

1.2

MutationAssessor

Pathogenic

4.4

PhyloP100

6.6

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-9.8

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.78

MVP

0.99

MPC

0.63

ClinPred

0.13

GERP RS

4.2

Varity_R

0.45

gMVP

0.97

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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