6-32196888-CT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004557.4(NOTCH4):c.5200+36del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,610,402 control chromosomes in the GnomAD database, including 4,397 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (1051 hom., cov: 31)
  • Exomes 𝑓: 0.058 (3346 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.896

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 -10 ACMG points.

• BP6: Variant 6-32196888-CT-C is Benign according to our data. Variant chr6-32196888-CT-C is described in ClinVar as [Benign]. Clinvar id is 1258765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.5200+36del		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.4908+36del		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.4806+36del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5200+36del		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000474612.1	n.3861+36del		intron_variant, non_coding_transcript_variant		5
NOTCH4	ENST00000491215.1	n.53+36del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0987 AC: 15006 AN: 152032 Hom.: 1047 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0823

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.0770 AC: 18896 AN: 245332 Hom.: 1036 AF XY: 0.0776 AC XY: 10375 AN XY: 133692

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.0595

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.139

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0406

Gnomad NFE exome AF: 0.0525

Gnomad OTH exome AF: 0.0696

GnomAD4 exome AF: 0.0581 AC: 84714 AN: 1458252 Hom.: 3346 Cov.: 31 AF XY: 0.0597 AC XY: 43292 AN XY: 725188

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0622

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0418

Gnomad4 NFE exome AF: 0.0474

Gnomad4 OTH exome AF: 0.0727

GnomAD4 genome AF: 0.0989 AC: 15049 AN: 152150 Hom.: 1051 Cov.: 31 AF XY: 0.0988 AC XY: 7349 AN XY: 74408

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0822

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0380

Gnomad4 NFE AF: 0.0502

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0708 Hom.: 109

Bravo AF: 0.107

Asia WGS AF: 0.161 AC: 559 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 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs35278224; hg19: chr6-32164665;