Genetic Variant NOTCH4:c.452-90C>T (chr6-32221415-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_004557.4(NOTCH4):c.452-90C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 915,768 control chromosomes in the GnomAD database, including 409 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 0.023 ( 54 hom., cov: 32)

Exomes 𝑓: 0.027 ( 355 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.447

Publications

9 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=-0.9).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0228 (3469/152232) while in subpopulation SAS AF = 0.0315 (152/4826). AF 95% confidence interval is 0.029. There are 54 homozygotes in GnomAd4. There are 1743 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
NOTCH4	NM_004557.4 link	c.452-90C>T	intron_variant	Intron 3 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 link	n.591-90C>T	intron_variant	Intron 3 of 29
NOTCH4	NR_134950.2 link	n.591-90C>T	intron_variant	Intron 3 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.452-90C>T		intron_variant	Intron 3 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1 link	n.581-90C>T		intron_variant	Intron 3 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3467

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.0317

Gnomad FIN

AF:

0.0357

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0300

Gnomad OTH

AF:

0.0315

GnomAD4 exome

AF:

0.0272

AC:

20741

AN:

763536

Hom.:

355

AF XY:

0.0279

AC XY:

10925

AN XY:

391672

show subpopulations

African (AFR)

AF:

0.00398

AC:

AN:

18836

American (AMR)

AF:

0.0230

AC:

569

AN:

24744

Ashkenazi Jewish (ASJ)

AF:

0.0347

AC:

561

AN:

16178

East Asian (EAS)

AF:

0.00558

AC:

195

AN:

34964

South Asian (SAS)

AF:

0.0336

AC:

1906

AN:

56660

European-Finnish (FIN)

AF:

0.0388

AC:

1510

AN:

38950

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

4232

European-Non Finnish (NFE)

AF:

0.0279

AC:

14833

AN:

532404

Other (OTH)

AF:

0.0279

AC:

1022

AN:

36568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1237

2475

3712

4950

6187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.0228

AC:

3469

AN:

152232

Hom.:

Cov.:

AF XY:

0.0234

AC XY:

1743

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00486

AC:

202

AN:

41534

American (AMR)

AF:

0.0262

AC:

400

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

126

AN:

3472

East Asian (EAS)

AF:

0.00406

AC:

AN:

5178

South Asian (SAS)

AF:

0.0315

AC:

152

AN:

4826

European-Finnish (FIN)

AF:

0.0357

AC:

379

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0300

AC:

2043

AN:

68002

Other (OTH)

AF:

0.0312

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

182

364

545

727

909

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:

0.0279

Hom.:

169

Bravo

AF:

0.0213

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.3

(source)

DANN

Benign

0.78

PhyloP100

0.45

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over