rs3830041

Variant names:

• chr6-32223562-C-T
• rs3830041
• NM_004557.4:c.73+294G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004557.4(NOTCH4):​c.73+294G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,026 control chromosomes in the GnomAD database, including 1,071 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 0.11 (1071 hom., cov: 31)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.588
• Publications: 42 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.73+294G>A		intron_variant	Intron 1 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.212+294G>A		intron_variant	Intron 1 of 29
NOTCH4	NR_134950.2	n.212+294G>A		intron_variant	Intron 1 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.73+294G>A		intron_variant	Intron 1 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.202+294G>A		intron_variant	Intron 1 of 10	1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16809 AN: 151908 Hom.: 1067 Cov.: 31

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.0975

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.0864

Gnomad OTH AF: 0.128

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

GnomAD4 genome AF: 0.111 AC: 16821 AN: 152026 Hom.: 1071 Cov.: 31 AF XY: 0.108 AC XY: 7994 AN XY: 74302

African (AFR) AF: 0.174 AC: 7216 AN: 41450

American (AMR) AF: 0.0973 AC: 1486 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3470

East Asian (EAS) AF: 0.122 AC: 627 AN: 5132

South Asian (SAS) AF: 0.111 AC: 534 AN: 4816

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10610

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0864 AC: 5870 AN: 67960

Other (OTH) AF: 0.128 AC: 270 AN: 2108

Alfa AF: 0.0951 Hom.: 2887

Bravo AF: 0.121

Asia WGS AF: 0.138 AC: 479 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.68
PhyloP100		0.59
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: rs3830041; hg19: chr6-32191339;