Variant 6-32220936-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_004557.4(NOTCH4):c.799+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,595,952 control chromosomes in the GnomAD database, including 548 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 0.020 ( 46 hom., cov: 33)

Exomes 𝑓: 0.024 ( 502 hom. )

Consequence

NOTCH4
NM_004557.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.450

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0197 (3004/152304) while in subpopulation SAS AF= 0.0313 (151/4828). AF 95% confidence interval is 0.0272. There are 46 homozygotes in gnomad4. There are 1531 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3004 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
NOTCH4	NM_004557.4 linkuse as main transcript	c.799+42G>C	intron_variant	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2 linkuse as main transcript	n.938+42G>C	intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2 linkuse as main transcript	n.938+42G>C	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3 linkuse as main transcript	c.799+42G>C		intron_variant		1	NM_004557.4	ENSP00000364163	P1	Q99466-1
NOTCH4	ENST00000473562.1 linkuse as main transcript	n.928+42G>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3006

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.00406

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.0357

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0262

Gnomad OTH

AF:

0.0296

GnomAD3 exomes

AF:

0.0251

AC:

5931

AN:

236178

Hom.:

119

AF XY:

0.0270

AC XY:

3431

AN XY:

127288

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0404

Gnomad EAS exome

AF:

0.00482

Gnomad SAS exome

AF:

0.0354

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0287

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0240

AC:

34638

AN:

1443648

Hom.:

502

Cov.:

AF XY:

0.0247

AC XY:

17668

AN XY:

716024

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.0155

Gnomad4 ASJ exome

AF:

0.0364

Gnomad4 EAS exome

AF:

0.00570

Gnomad4 SAS exome

AF:

0.0339

Gnomad4 FIN exome

AF:

0.0380

Gnomad4 NFE exome

AF:

0.0240

Gnomad4 OTH exome

AF:

0.0241

GnomAD4 genome

AF:

0.0197

AC:

3004

AN:

152304

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1531

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00368

Gnomad4 AMR

AF:

0.0212

Gnomad4 ASJ

AF:

0.0357

Gnomad4 EAS

AF:

0.00407

Gnomad4 SAS

AF:

0.0313

Gnomad4 FIN

AF:

0.0357

Gnomad4 NFE

AF:

0.0262

Gnomad4 OTH

AF:

0.0293

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0176

Asia WGS

AF:

0.00953

AC:

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

8.6

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over