rs367398

Variant names:

• chr6-32223953-G-A
• rs367398
• NM_004557.4:c.-25C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 26 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=-0.81).
• 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 rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NM_004557.4	c.-25C>T		5_prime_UTR_variant	Exon 1 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.115C>T		non_coding_transcript_exon_variant	Exon 1 of 30
NOTCH4	NR_134950.2	n.115C>T		non_coding_transcript_exon_variant	Exon 1 of 29

Ensembl

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

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

GnomAD2 exomes AF: 0.344 AC: 71097 AN: 206586 AF XY: 0.346

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 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

African (AFR) AF: 0.570 AC: 18498 AN: 32478

American (AMR) AF: 0.400 AC: 16185 AN: 40494

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 10238 AN: 23896

East Asian (EAS) AF: 0.406 AC: 15512 AN: 38208

South Asian (SAS) AF: 0.419 AC: 34398 AN: 82066

European-Finnish (FIN) AF: 0.232 AC: 9726 AN: 41886

Middle Eastern (MID) AF: 0.473 AC: 2631 AN: 5566

European-Non Finnish (NFE) AF: 0.306 AC: 335769 AN: 1097140

Other (OTH) AF: 0.336 AC: 19810 AN: 58876

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

African (AFR) AF: 0.567 AC: 23392 AN: 41242

American (AMR) AF: 0.418 AC: 6358 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1600 AN: 3468

East Asian (EAS) AF: 0.337 AC: 1714 AN: 5088

South Asian (SAS) AF: 0.402 AC: 1928 AN: 4794

European-Finnish (FIN) AF: 0.233 AC: 2445 AN: 10476

Middle Eastern (MID) AF: 0.452 AC: 131 AN: 290

European-Non Finnish (NFE) AF: 0.315 AC: 21370 AN: 67828

Other (OTH) AF: 0.422 AC: 883 AN: 2090

Alfa AF: 0.352 Hom.: 3326

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
PhyloP100		0.72
PromoterAI		-0.086	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs367398; hg19: chr6-32191730; COSMIC: COSV66681391;