Genetic Variant NOTCH4:n.2367A>G (chr6-32216568-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000473562.1(NOTCH4):n.2367A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 339,092 control chromosomes in the GnomAD database, including 7,245 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.21 ( 3782 hom., cov: 33)

Exomes 𝑓: 0.17 ( 3463 hom. )

Consequence

NOTCH4
ENST00000473562.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.812

Publications

78 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
NOTCH4	NM_004557.4 link	c.1861+377A>G	intron_variant	Intron 11 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 link	n.2102+377A>G	intron_variant	Intron 12 of 29
NOTCH4	NR_134950.2 link	n.2000+377A>G	intron_variant	Intron 11 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000473562.1 link	n.2367A>G		non_coding_transcript_exon_variant	Exon 11 of 11	1
NOTCH4	ENST00000375023.3 link	c.1861+377A>G		intron_variant	Intron 11 of 29	1	NM_004557.4	ENSP00000364163.3

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31868

AN:

152154

Hom.:

3778

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.213

GnomAD4 exome

AF:

0.173

AC:

32405

AN:

186820

Hom.:

3463

Cov.:

AF XY:

0.173

AC XY:

17245

AN XY:

99910

show subpopulations

African (AFR)

AF:

0.277

AC:

1545

AN:

5570

American (AMR)

AF:

0.194

AC:

1460

AN:

7530

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

1168

AN:

5116

East Asian (EAS)

AF:

0.431

AC:

3543

AN:

8222

South Asian (SAS)

AF:

0.161

AC:

4855

AN:

30126

European-Finnish (FIN)

AF:

0.0980

AC:

845

AN:

8626

Middle Eastern (MID)

AF:

0.183

AC:

135

AN:

738

European-Non Finnish (NFE)

AF:

0.154

AC:

17147

AN:

111124

Other (OTH)

AF:

0.175

AC:

1707

AN:

9768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1163

2325

3488

4650

5813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.210

AC:

31909

AN:

152272

Hom.:

3782

Cov.:

AF XY:

0.206

AC XY:

15325

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.296

AC:

12275

AN:

41532

American (AMR)

AF:

0.189

AC:

2892

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

776

AN:

3472

East Asian (EAS)

AF:

0.438

AC:

2267

AN:

5180

South Asian (SAS)

AF:

0.186

AC:

899

AN:

4826

European-Finnish (FIN)

AF:

0.110

AC:

1164

AN:

10616

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.162

AC:

11012

AN:

68022

Other (OTH)

AF:

0.216

AC:

457

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1277

2554

3832

5109

6386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.177

Hom.:

9943

Bravo

AF:

0.223

Asia WGS

AF:

0.263

AC:

912

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.24

(source)

DANN

Benign

0.70

PhyloP100

-0.81

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over