Genetic Variant NOTCH4:c.74-178C>T (chr6-32223264-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_004557.4(NOTCH4):c.74-178C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,746 control chromosomes in the GnomAD database, including 7,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.31 ( 7387 hom., cov: 30)

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.238

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 6-32223264-G-A is Benign according to our data. Variant chr6-32223264-G-A is described in ClinVar as [Benign]. Clinvar id is 1236049.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.74-178C>T	intron_variant	Intron 1 of 29	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.213-178C>T	intron_variant	Intron 1 of 29
NOTCH4	NR_134950.2 link	n.213-178C>T	intron_variant	Intron 1 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.74-178C>T		intron_variant	Intron 1 of 29	1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000473562.1 link	n.203-178C>T		intron_variant	Intron 1 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

46935

AN:

151630

Hom.:

7382

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.300

Gnomad OTH

AF:

0.310

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

GnomAD4 genome

AF:

0.310

AC:

46979

AN:

151746

Hom.:

7387

Cov.:

AF XY:

0.308

AC XY:

22860

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.306

AC:

12657

AN:

41356

American (AMR)

AF:

0.282

AC:

4314

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.441

AC:

1531

AN:

3468

East Asian (EAS)

AF:

0.476

AC:

2435

AN:

5120

South Asian (SAS)

AF:

0.256

AC:

1230

AN:

4798

European-Finnish (FIN)

AF:

0.316

AC:

3321

AN:

10522

Middle Eastern (MID)

AF:

0.271

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.300

AC:

20377

AN:

67904

Other (OTH)

AF:

0.307

AC:

646

AN:

2102

Heterozygous variant carriers

1624

3249

4873

6498

8122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.327

Hom.:

10365

Bravo

AF:

0.311

Asia WGS

AF:

0.350

AC:

1220

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.2

DANN

Benign

0.67

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over