Genetic Variant NOTCH4:c.73+294G>A (chr6-32223562-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.73+294G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,026 control chromosomes in the GnomAD database, including 1,071 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 ( 1071 hom., cov: 31)

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.588

Publications

42 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=-0.8).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 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.73+294G>A	intron	N/A	NP_004548.3
NOTCH4	NR_134949.2		n.212+294G>A	intron	N/A
NOTCH4	NR_134950.2		n.212+294G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.73+294G>A	intron	N/A	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000473562.1	TSL:1	n.202+294G>A	intron	N/A
NOTCH4	ENST00000883244.1		c.73+294G>A	intron	N/A	ENSP00000553303.1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16809

AN:

151908

Hom.:

1067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.0975

Gnomad ASJ

AF:

0.0971

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.111

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.0864

Gnomad OTH

AF:

0.128

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

GnomAD4 genome

AF:

0.111

AC:

16821

AN:

152026

Hom.:

1071

Cov.:

AF XY:

0.108

AC XY:

7994

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.174

AC:

7216

AN:

41450

American (AMR)

AF:

0.0973

AC:

1486

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0971

AC:

337

AN:

3470

East Asian (EAS)

AF:

0.122

AC:

627

AN:

5132

South Asian (SAS)

AF:

0.111

AC:

534

AN:

4816

European-Finnish (FIN)

AF:

0.0250

AC:

265

AN:

10610

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0864

AC:

5870

AN:

67960

Other (OTH)

AF:

0.128

AC:

270

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

751

1503

2254

3006

3757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.0951

Hom.:

2887

Bravo

AF:

0.121

Asia WGS

AF:

0.138

AC:

479

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.5

(source)

DANN

Benign

0.68

PhyloP100

0.59

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