rs2854050

Positions:

• chr6-32217828-G-A

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.1624+167C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 152,298 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.056 (333 hom., cov: 32)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.74

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=-0.79).
• BP6: Variant 6-32217828-G-A is Benign according to our data. Variant chr6-32217828-G-A is described in ClinVar as [Benign]. Clinvar id is 1273884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.1624+167C>T		intron_variant		ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.1865+167C>T		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.1763+167C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.1624+167C>T		intron_variant		1	NM_004557.4	ENSP00000364163	P1
NOTCH4	ENST00000473562.1	n.1753+167C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8572 AN: 152180 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0581

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0659

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

GnomAD4 genome AF: 0.0564 AC: 8584 AN: 152298 Hom.: 333 Cov.: 32 AF XY: 0.0558 AC XY: 4159 AN XY: 74478

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.0694

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.0681

Alfa AF: 0.0608 Hom.: 545

Bravo AF: 0.0598

Asia WGS AF: 0.0790 AC: 275 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	-0.79
CADD	Benign	9.2
DANN	Benign	0.66

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: rs2854050; hg19: chr6-32185605; COSMIC: COSV66679014; COSMIC: COSV66679014;