rs384247

Positions:

• chr6-32216797-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000375023.3(NOTCH4):​c.1861+148C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 986,634 control chromosomes in the GnomAD database, including 18,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3631 hom., cov: 33)
  • Exomes 𝑓: 0.18 (14981 hom.)
• Consequence: NOTCH4 ENST00000375023.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.31

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-32216797-G-A is Benign according to our data. Variant chr6-32216797-G-A is described in ClinVar as [Benign]. Clinvar id is 1248031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1861+148C>T		intron_variant		ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2102+148C>T		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.2000+148C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1861+148C>T		intron_variant		1	NM_004557.4	ENSP00000364163	P1
NOTCH4	ENST00000473562.1	n.2138C>T		non_coding_transcript_exon_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31523 AN: 152076 Hom.: 3627 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.178 AC: 148691 AN: 834442 Hom.: 14981 Cov.: 11 AF XY: 0.176 AC XY: 76829 AN XY: 436222

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.207 AC: 31562 AN: 152192 Hom.: 3631 Cov.: 33 AF XY: 0.203 AC XY: 15121 AN XY: 74408

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.214

Alfa AF: 0.170 Hom.: 665

Bravo AF: 0.221

Asia WGS AF: 0.238 AC: 827 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.8
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs384247; hg19: chr6-32184574;