NM_004557.4:c.74-178C>T

Variant names:

• chr6-32223264-G-A
• rs434841
• NM_004557.4:c.74-178C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):​c.74-178C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,746 control chromosomes in the GnomAD database, including 7,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7387 hom., cov: 30)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.238
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-32223264-G-A is Benign according to our data. Variant chr6-32223264-G-A is described in ClinVar as Benign. ClinVar VariationId is 1236049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.74-178C>T		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.213-178C>T		intron	N/A
	NOTCH4	NR_134950.2		n.213-178C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.74-178C>T		intron	N/A	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000473562.1	TSL:1	n.203-178C>T		intron	N/A
	NOTCH4	ENST00000883244.1		c.74-178C>T		intron	N/A	ENSP00000553303.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 46935 AN: 151630 Hom.: 7382 Cov.: 30

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.310 AC: 46979 AN: 151746 Hom.: 7387 Cov.: 30 AF XY: 0.308 AC XY: 22860 AN XY: 74132

African (AFR) AF: 0.306 AC: 12657 AN: 41356

American (AMR) AF: 0.282 AC: 4314 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1531 AN: 3468

East Asian (EAS) AF: 0.476 AC: 2435 AN: 5120

South Asian (SAS) AF: 0.256 AC: 1230 AN: 4798

European-Finnish (FIN) AF: 0.316 AC: 3321 AN: 10522

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.300 AC: 20377 AN: 67904

Other (OTH) AF: 0.307 AC: 646 AN: 2102

Alfa AF: 0.327 Hom.: 10365

Bravo AF: 0.311

Asia WGS AF: 0.350 AC: 1220 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.67
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs434841; hg19: chr6-32191041; COSMIC: COSV66684940;