dbSNP rs384247: NOTCH4:n.2138C>T (chr6-32216797-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 ENST00000473562.1(NOTCH4):n.2138C>T 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 0.183 in 986,634 control chromosomes in the GnomAD database, including 18,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.21 ( 3631 hom., cov: 33)

Exomes 𝑓: 0.18 ( 14981 hom. )

Consequence

NOTCH4
ENST00000473562.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.31

Publications

25 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 6-32216797-G-A is Benign according to our data. Variant chr6-32216797-G-A is described in ClinVar as Benign. ClinVar VariationId is 1248031.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
NOTCH4	NM_004557.4 link	c.1861+148C>T	intron_variant	Intron 11 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 link	n.2102+148C>T	intron_variant	Intron 12 of 29
NOTCH4	NR_134950.2 link	n.2000+148C>T	intron_variant	Intron 11 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000473562.1 link	n.2138C>T		non_coding_transcript_exon_variant	Exon 11 of 11	1
NOTCH4	ENST00000375023.3 link	c.1861+148C>T		intron_variant	Intron 11 of 29	1	NM_004557.4	ENSP00000364163.3

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

31523

AN:

152076

Hom.:

3627

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.211

GnomAD4 exome

AF:

0.178

AC:

148691

AN:

834442

Hom.:

14981

Cov.:

AF XY:

0.176

AC XY:

76829

AN XY:

436222

show subpopulations

African (AFR)

AF:

0.294

AC:

6198

AN:

21054

American (AMR)

AF:

0.210

AC:

8364

AN:

39888

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

4718

AN:

20754

East Asian (EAS)

AF:

0.388

AC:

14005

AN:

36080

South Asian (SAS)

AF:

0.165

AC:

11321

AN:

68788

European-Finnish (FIN)

AF:

0.106

AC:

4859

AN:

45868

Middle Eastern (MID)

AF:

0.157

AC:

706

AN:

4504

European-Non Finnish (NFE)

AF:

0.163

AC:

91064

AN:

557780

Other (OTH)

AF:

0.188

AC:

7456

AN:

39726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

6299

12598

18897

25196

31495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2326

4652

6978

9304

11630

<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:

0.207

AC:

31562

AN:

152192

Hom.:

3631

Cov.:

AF XY:

0.203

AC XY:

15121

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.296

AC:

12268

AN:

41482

American (AMR)

AF:

0.189

AC:

2892

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

775

AN:

3468

East Asian (EAS)

AF:

0.377

AC:

1954

AN:

5184

South Asian (SAS)

AF:

0.181

AC:

875

AN:

4822

European-Finnish (FIN)

AF:

0.110

AC:

1163

AN:

10596

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.162

AC:

11016

AN:

68018

Other (OTH)

AF:

0.214

AC:

452

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1291

2582

3872

5163

6454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.178

Hom.:

5249

Bravo

AF:

0.221

Asia WGS

AF:

0.238

AC:

827

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

-0.80

CADD

Benign

7.8

(source)

DANN

Benign

0.81

PhyloP100

1.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over