rs8192581

Variant names:

• chr6-32195887-C-A
• rs8192581
• NM_004557.4:c.5562G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32195887-C-A
• chr6-32195887-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004557.4(NOTCH4):​c.5562G>T​(p.Gly1854Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1854G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=0.132 with no splicing effect.

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.5562G>T	p.Gly1854Gly	synonymous	Exon 30 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.5270G>T		non_coding_transcript_exon	Exon 30 of 30
	NOTCH4	NR_134950.2		n.5168G>T		non_coding_transcript_exon	Exon 29 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.5562G>T	p.Gly1854Gly	synonymous	Exon 30 of 30	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.5553G>T	p.Gly1851Gly	synonymous	Exon 30 of 30	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.5430G>T	p.Gly1810Gly	synonymous	Exon 29 of 29	ENSP00000553304.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 43384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 85234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107740

Other (OTH) AF: 0.00 AC: 0 AN: 59786

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.8
DANN	Benign	0.96
PhyloP100		0.13
PromoterAI		-0.28	Neutral

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: rs8192581; hg19: chr6-32163664;