6-32210103-C-G

Variant names:

• chr6-32210103-C-G
• rs206018
• NM_004557.4:c.2865+649G>C

Variant summary

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

The NM_004557.4(NOTCH4):​c.2865+649G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,060 control chromosomes in the GnomAD database, including 3,277 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 0.20 (3277 hom., cov: 32)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562
• Publications: 22 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2865+649G>C		intron_variant	Intron 18 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.3106+649G>C		intron_variant	Intron 19 of 29
NOTCH4	NR_134950.2	n.3004+649G>C		intron_variant	Intron 18 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2865+649G>C		intron_variant	Intron 18 of 29	1	NM_004557.4	ENSP00000364163.3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30983 AN: 151942 Hom.: 3272 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.204 AC: 31038 AN: 152060 Hom.: 3277 Cov.: 32 AF XY: 0.208 AC XY: 15460 AN XY: 74344

African (AFR) AF: 0.224 AC: 9291 AN: 41440

American (AMR) AF: 0.270 AC: 4118 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3470

East Asian (EAS) AF: 0.193 AC: 998 AN: 5184

South Asian (SAS) AF: 0.178 AC: 860 AN: 4820

European-Finnish (FIN) AF: 0.257 AC: 2716 AN: 10576

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12086 AN: 67978

Other (OTH) AF: 0.201 AC: 424 AN: 2112

Alfa AF: 0.152 Hom.: 1117

Bravo AF: 0.208

Asia WGS AF: 0.210 AC: 727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.46
PhyloP100		-0.56
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: rs206018; hg19: chr6-32177880;