rs8192565

chr6-32223830-C-T

Variant summary

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

The NM_004557.4(NOTCH4):c.73+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,587,900 control chromosomes in the GnomAD database, including 7,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.086 (684 hom., cov: 30)
  • Exomes 𝑓: 0.088 (6419 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.356

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=-0.85).
• BP6: Variant 6-32223830-C-T is Benign according to our data. Variant chr6-32223830-C-T is described in ClinVar as [Benign]. Clinvar id is 1275095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.73+26G>A		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.212+26G>A		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.212+26G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.73+26G>A		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000473562.1	n.202+26G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0858 AC: 13033 AN: 151866 Hom.: 679 Cov.: 30

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0953

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0984

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.0929

GnomAD3 exomes AF: 0.0781 AC: 17784 AN: 227736 Hom.: 923 AF XY: 0.0806 AC XY: 10032 AN XY: 124470

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0591

Gnomad SAS exome AF: 0.0918

Gnomad FIN exome AF: 0.0885

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0884 AC: 126976 AN: 1435916 Hom.: 6419 Cov.: 30 AF XY: 0.0895 AC XY: 63876 AN XY: 713836

Gnomad4 AFR exome AF: 0.0326

Gnomad4 AMR exome AF: 0.0825

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0962

Gnomad4 NFE exome AF: 0.0854

Gnomad4 OTH exome AF: 0.0896

GnomAD4 genome AF: 0.0858 AC: 13039 AN: 151984 Hom.: 684 Cov.: 30 AF XY: 0.0882 AC XY: 6548 AN XY: 74258

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.0946

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0984

Gnomad4 NFE AF: 0.0940

Gnomad4 OTH AF: 0.0995

Alfa AF: 0.0943 Hom.: 812

Bravo AF: 0.0823

Asia WGS AF: 0.171 AC: 596 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 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.0
Dann	Benign	0.42

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: rs8192565; hg19: chr6-32191607; COSMIC: COSV66678825;