chr6-32216568-T-C

Position:

• chr6-32216568-T-C

Variant summary

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

The NM_004557.4(NOTCH4):​c.1861+377A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 339,092 control chromosomes in the GnomAD database, including 7,245 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 0.21 (3782 hom., cov: 33)
  • Exomes 𝑓: 0.17 (3463 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.812

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1861+377A>G		intron_variant		ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2102+377A>G		intron_variant
NOTCH4	NR_134950.2	n.2000+377A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1861+377A>G		intron_variant		1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.2367A>G		non_coding_transcript_exon_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31868 AN: 152154 Hom.: 3778 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.173 AC: 32405 AN: 186820 Hom.: 3463 Cov.: 0 AF XY: 0.173 AC XY: 17245 AN XY: 99910

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.0980

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.210 AC: 31909 AN: 152272 Hom.: 3782 Cov.: 33 AF XY: 0.206 AC XY: 15325 AN XY: 74462

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.216

Alfa AF: 0.177 Hom.: 4538

Bravo AF: 0.223

Asia WGS AF: 0.263 AC: 912 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	0.24
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs404860; hg19: chr6-32184345;