rs2854050

Variant names:

• chr6-32217828-G-A
• rs2854050
• NM_004557.4:c.1624+167C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32217828-G-A
• chr6-32217828-G-C
• chr6-32217828-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 39 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004557.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.1624+167C>T		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.1865+167C>T		intron	N/A
	NOTCH4	NR_134950.2		n.1763+167C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.1624+167C>T		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000473562.1	TSL:1	n.1753+167C>T		intron	N/A

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

African (AFR) AF: 0.0367 AC: 1527 AN: 41570

American (AMR) AF: 0.0585 AC: 896 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3470

East Asian (EAS) AF: 0.195 AC: 1009 AN: 5170

South Asian (SAS) AF: 0.0694 AC: 335 AN: 4828

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3813 AN: 68016

Other (OTH) AF: 0.0681 AC: 144 AN: 2116

Alfa AF: 0.0593 Hom.: 1163

Bravo AF: 0.0598

Asia WGS AF: 0.0790 AC: 275 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.2
DANN	Benign	0.66
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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