NM_004557.4:c.452-90C>T

Variant names:

• chr6-32221415-G-A
• rs8192584
• NM_004557.4:c.452-90C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3469 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.452-90C>T		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.591-90C>T		intron	N/A
	NOTCH4	NR_134950.2		n.591-90C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.452-90C>T		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000473562.1	TSL:1	n.581-90C>T		intron	N/A

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

African (AFR) AF: 0.00398 AC: 75 AN: 18836

American (AMR) AF: 0.0230 AC: 569 AN: 24744

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 561 AN: 16178

East Asian (EAS) AF: 0.00558 AC: 195 AN: 34964

South Asian (SAS) AF: 0.0336 AC: 1906 AN: 56660

European-Finnish (FIN) AF: 0.0388 AC: 1510 AN: 38950

Middle Eastern (MID) AF: 0.0165 AC: 70 AN: 4232

European-Non Finnish (NFE) AF: 0.0279 AC: 14833 AN: 532404

Other (OTH) AF: 0.0279 AC: 1022 AN: 36568

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

African (AFR) AF: 0.00486 AC: 202 AN: 41534

American (AMR) AF: 0.0262 AC: 400 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3472

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5178

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4826

European-Finnish (FIN) AF: 0.0357 AC: 379 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0300 AC: 2043 AN: 68002

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0279 Hom.: 169

Bravo AF: 0.0213

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.78
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs8192584; hg19: chr6-32189192;