rs8192584

Positions:

• chr6-32221415-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004557.4(NOTCH4):​c.452-90C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 915,768 control chromosomes in the GnomAD database, including 409 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 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.027 (355 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0228 (3469/152232) while in subpopulation SAS AF= 0.0315 (152/4826). AF 95% confidence interval is 0.029. There are 54 homozygotes in gnomad4. There are 1743 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.452-90C>T		intron_variant		ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.591-90C>T		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.591-90C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.452-90C>T		intron_variant		1	NM_004557.4	ENSP00000364163	P1
NOTCH4	ENST00000473562.1	n.581-90C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3467 AN: 152114 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.0272 AC: 20741 AN: 763536 Hom.: 355 AF XY: 0.0279 AC XY: 10925 AN XY: 391672

Gnomad4 AFR exome AF: 0.00398

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.00558

Gnomad4 SAS exome AF: 0.0336

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0279

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0228 AC: 3469 AN: 152232 Hom.: 54 Cov.: 32 AF XY: 0.0234 AC XY: 1743 AN XY: 74426

Gnomad4 AFR AF: 0.00486

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.0363

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0300

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0279 Hom.: 61

Bravo AF: 0.0213

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.78

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

Other links and lift over

dbSNP: rs8192584; hg19: chr6-32189192;