Genetic Variant NOTCH4:p.Gly1854Gly (chr6-32195887-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_004557.4(NOTCH4):c.5562G>A(p.Gly1854Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 1,590,470 control chromosomes in the GnomAD database, including 786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0063 ( 36 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 750 hom. )

Consequence

NOTCH4
NM_004557.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.132

Publications

2 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 6-32195887-C-T is Benign according to our data. Variant chr6-32195887-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277130.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.132 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0793 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	HGVSp	Effect	Exon Rank	Protein
NOTCH4	NM_004557.4	MANE Select	c.5562G>A	p.Gly1854Gly	synonymous	Exon 30 of 30	NP_004548.3
NOTCH4	NR_134949.2		n.5270G>A		non_coding_transcript_exon	Exon 30 of 30
NOTCH4	NR_134950.2		n.5168G>A		non_coding_transcript_exon	Exon 29 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.5562G>A	p.Gly1854Gly	synonymous	Exon 30 of 30	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000883244.1		c.5553G>A	p.Gly1851Gly	synonymous	Exon 30 of 30	ENSP00000553303.1
NOTCH4	ENST00000883245.1		c.5430G>A	p.Gly1810Gly	synonymous	Exon 29 of 29	ENSP00000553304.1

Frequencies

GnomAD3 genomes

AF:

0.00629

AC:

958

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00538

Gnomad SAS

AF:

0.0855

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0191

AC:

3941

AN:

206292

AF XY:

0.0259

show subpopulations

Gnomad AFR exome

AF:

0.00282

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.00632

Gnomad EAS exome

AF:

0.00362

Gnomad FIN exome

AF:

0.000486

Gnomad NFE exome

AF:

0.00448

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.00951

AC:

13671

AN:

1438112

Hom.:

750

Cov.:

AF XY:

0.0133

AC XY:

9496

AN XY:

715236

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

33242

American (AMR)

AF:

0.00452

AC:

196

AN:

43384

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

194

AN:

25862

East Asian (EAS)

AF:

0.00216

AC:

AN:

39338

South Asian (SAS)

AF:

0.106

AC:

9023

AN:

85232

European-Finnish (FIN)

AF:

0.000397

AC:

AN:

37792

Middle Eastern (MID)

AF:

0.0655

AC:

376

AN:

5738

European-Non Finnish (NFE)

AF:

0.00288

AC:

3185

AN:

1107738

Other (OTH)

AF:

0.00873

AC:

522

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

901

1802

2703

3604

4505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00628

AC:

957

AN:

152358

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

600

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00272

AC:

113

AN:

41586

American (AMR)

AF:

0.00464

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00520

AC:

AN:

5188

South Asian (SAS)

AF:

0.0862

AC:

416

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00392

AC:

267

AN:

68028

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00585

Hom.:

Bravo

AF:

0.00435

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.5

(source)

DANN

Uncertain

0.97

PhyloP100

0.13

PromoterAI

-0.032

Neutral

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over