rs367398

Positions:

• chr6-32223953-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004557.4(NOTCH4):​c.-25C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,572,000 control chromosomes in the GnomAD database, including 93,006 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 0.40 (13095 hom., cov: 29)
  • Exomes 𝑓: 0.33 (79911 hom.)
• Consequence: NOTCH4 NM_004557.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.717

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	1/30	ENST00000375023.3	NP_004548.3
NOTCH4	NM_004557.4	c.-25C>T		5_prime_UTR_variant	1/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.115C>T		non_coding_transcript_exon_variant	1/30
NOTCH4	NR_134950.2	n.115C>T		non_coding_transcript_exon_variant	1/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	1/30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000375023.3	c.-25C>T		5_prime_UTR_variant	1/30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.105C>T		non_coding_transcript_exon_variant	1/11	1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60162 AN: 151274 Hom.: 13066 Cov.: 29

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.421

GnomAD3 exomes AF: 0.344 AC: 71097 AN: 206586 Hom.: 13663 AF XY: 0.346 AC XY: 39340 AN XY: 113638

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.301

Gnomad SAS exome AF: 0.417

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.326 AC: 462767 AN: 1420610 Hom.: 79911 Cov.: 35 AF XY: 0.329 AC XY: 232112 AN XY: 705814

Gnomad4 AFR exome AF: 0.570

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.406

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.398 AC: 60239 AN: 151390 Hom.: 13095 Cov.: 29 AF XY: 0.396 AC XY: 29277 AN XY: 73922

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.422

Alfa AF: 0.340 Hom.: 2819

Bravo AF: 0.419

Asia WGS AF: 0.396 AC: 1376 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs367398; hg19: chr6-32191730; COSMIC: COSV66681391;