Genetic Variant NOTCH4:c.2866-827G>A (chr6-32205216-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_004557.4(NOTCH4):c.2866-827G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 151,500 control chromosomes in the GnomAD database, including 982 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 0.11 ( 982 hom., cov: 31)

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.703

Publications

124 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=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 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	Effect	Exon Rank	Protein
NOTCH4	NM_004557.4	MANE Select	c.2866-827G>A	intron	N/A	NP_004548.3
NOTCH4	NR_134949.2		n.3107-827G>A	intron	N/A
NOTCH4	NR_134950.2		n.3005-827G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.2866-827G>A	intron	N/A	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000883244.1		c.2866-827G>A	intron	N/A	ENSP00000553303.1
NOTCH4	ENST00000883245.1		c.2743-827G>A	intron	N/A	ENSP00000553304.1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16068

AN:

151386

Hom.:

982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0913

Gnomad AMI

AF:

0.0736

Gnomad AMR

AF:

0.0546

Gnomad ASJ

AF:

0.0767

Gnomad EAS

AF:

0.0328

Gnomad SAS

AF:

0.0962

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.0910

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.106

AC:

16065

AN:

151500

Hom.:

982

Cov.:

AF XY:

0.103

AC XY:

7625

AN XY:

73976

show subpopulations

African (AFR)

AF:

0.0912

AC:

3784

AN:

41480

American (AMR)

AF:

0.0543

AC:

829

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0767

AC:

266

AN:

3468

East Asian (EAS)

AF:

0.0331

AC:

155

AN:

4678

South Asian (SAS)

AF:

0.0955

AC:

455

AN:

4766

European-Finnish (FIN)

AF:

0.117

AC:

1237

AN:

10564

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9068

AN:

67976

Other (OTH)

AF:

0.0900

AC:

189

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

722

1444

2165

2887

3609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.129

Hom.:

4969

Bravo

AF:

0.101

Asia WGS

AF:

0.0550

AC:

193

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

8.2

(source)

DANN

Benign

0.49

PhyloP100

0.70

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over