Genetic Variant NOTCH4:c.3231+472T>C (chr6-32203298-A-G) – 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.3231+472T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 155,664 control chromosomes in the GnomAD database, including 2,886 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 0.19 ( 2812 hom., cov: 32)

Exomes 𝑓: 0.16 ( 74 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.840

Publications

40 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=-0.82).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4 link	c.3231+472T>C	intron_variant	Intron 20 of 29	ENST00000375023.3	NP_004548.3	Q99466-1A0A1U9X983
NOTCH4	NR_134949.2 link	n.3472+472T>C	intron_variant	Intron 21 of 29
NOTCH4	NR_134950.2 link	n.3370+472T>C	intron_variant	Intron 20 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 link	c.3231+472T>C		intron_variant	Intron 20 of 29	1	NM_004557.4	ENSP00000364163.3		Q99466-1
NOTCH4	ENST00000474612.1 link	n.619T>C		non_coding_transcript_exon_variant	Exon 2 of 10	5

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28597

AN:

152094

Hom.:

2816

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.253

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.178

GnomAD4 exome

AF:

0.157

AC:

543

AN:

3452

Hom.:

Cov.:

AF XY:

0.166

AC XY:

299

AN XY:

1802

show subpopulations

African (AFR)

AF:

0.191

AC:

AN:

110

American (AMR)

AF:

0.0658

AC:

AN:

152

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

AN:

110

East Asian (EAS)

AF:

0.158

AC:

AN:

South Asian (SAS)

AF:

0.174

AC:

AN:

138

European-Finnish (FIN)

AF:

0.131

AC:

AN:

122

Middle Eastern (MID)

AF:

0.0833

AC:

AN:

European-Non Finnish (NFE)

AF:

0.162

AC:

407

AN:

2508

Other (OTH)

AF:

0.156

AC:

AN:

224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.188

AC:

28592

AN:

152212

Hom.:

2812

Cov.:

AF XY:

0.186

AC XY:

13819

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.178

AC:

7382

AN:

41510

American (AMR)

AF:

0.134

AC:

2047

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

633

AN:

3472

East Asian (EAS)

AF:

0.183

AC:

947

AN:

5184

South Asian (SAS)

AF:

0.252

AC:

1216

AN:

4834

European-Finnish (FIN)

AF:

0.160

AC:

1694

AN:

10582

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.206

AC:

14028

AN:

68016

Other (OTH)

AF:

0.176

AC:

372

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1219

2439

3658

4878

6097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.202

Hom.:

8793

Bravo

AF:

0.185

Asia WGS

AF:

0.173

AC:

603

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.2

(source)

DANN

Benign

0.85

PhyloP100

0.84

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

Computational scores

Splicing

Publications

Other links and lift over