rs520803

Variant names:

• chr6-32220826-C-T
• rs520803
• NM_004557.4:c.852G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32220826-C-T
• chr6-32220826-C-A
• chr6-32220826-C-G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004557.4(NOTCH4):​c.852G>A​(p.Gln284Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,788 control chromosomes in the GnomAD database, including 76,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6864 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69551 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.33
• Publications: 36 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-32220826-C-T is Benign according to our data. Variant chr6-32220826-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.852G>A	p.Gln284Gln	synonymous	Exon 5 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.991G>A		non_coding_transcript_exon	Exon 5 of 30
	NOTCH4	NR_134950.2		n.991G>A		non_coding_transcript_exon	Exon 5 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.852G>A	p.Gln284Gln	synonymous	Exon 5 of 30	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000473562.1	TSL:1	n.981G>A		non_coding_transcript_exon	Exon 5 of 11
	NOTCH4	ENST00000883244.1		c.852G>A	p.Gln284Gln	synonymous	Exon 5 of 30	ENSP00000553303.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44182 AN: 151982 Hom.: 6862 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.306 AC: 76887 AN: 251330 AF XY: 0.315

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.508

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.334

GnomAD4 exome AF: 0.303 AC: 442177 AN: 1461688 Hom.: 69551 Cov.: 52 AF XY: 0.306 AC XY: 222572 AN XY: 727156

African (AFR) AF: 0.218 AC: 7283 AN: 33478

American (AMR) AF: 0.269 AC: 12018 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 13104 AN: 26130

East Asian (EAS) AF: 0.190 AC: 7552 AN: 39700

South Asian (SAS) AF: 0.330 AC: 28470 AN: 86240

European-Finnish (FIN) AF: 0.308 AC: 16476 AN: 53414

Middle Eastern (MID) AF: 0.396 AC: 2285 AN: 5766

European-Non Finnish (NFE) AF: 0.302 AC: 336234 AN: 1111870

Other (OTH) AF: 0.311 AC: 18755 AN: 60382

GnomAD4 genome AF: 0.290 AC: 44184 AN: 152100 Hom.: 6864 Cov.: 33 AF XY: 0.291 AC XY: 21654 AN XY: 74368

African (AFR) AF: 0.211 AC: 8771 AN: 41506

American (AMR) AF: 0.322 AC: 4927 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1758 AN: 3468

East Asian (EAS) AF: 0.164 AC: 846 AN: 5164

South Asian (SAS) AF: 0.316 AC: 1522 AN: 4822

European-Finnish (FIN) AF: 0.314 AC: 3324 AN: 10592

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21884 AN: 67944

Other (OTH) AF: 0.316 AC: 666 AN: 2110

Alfa AF: 0.317 Hom.: 10824

Bravo AF: 0.286

Asia WGS AF: 0.321 AC: 1121 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.362

ClinVar

ClinVar submissions

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	-0.87
CADD	Benign	0.67
DANN	Benign	0.40
PhyloP100		-3.3
Mutation Taster		=99/1	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: rs520803; hg19: chr6-32188603; COSMIC: COSV66678390;