rs2269418

Variant names:

• chr6-32212343-T-G
• rs2269418
• NM_004557.4:c.2680+131A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004557.4(NOTCH4):​c.2680+131A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 804,876 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (118 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.130
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.055 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.2680+131A>C		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.2921+131A>C		intron	N/A
	NOTCH4	NR_134950.2		n.2819+131A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.2680+131A>C		intron	N/A	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.2680+131A>C		intron	N/A	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.2557+131A>C		intron	N/A	ENSP00000553304.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152182 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0602

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00482 AC: 3145 AN: 652576 Hom.: 118 AF XY: 0.00474 AC XY: 1604 AN XY: 338044

African (AFR) AF: 0.000179 AC: 3 AN: 16746

American (AMR) AF: 0.00 AC: 0 AN: 20792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14936

East Asian (EAS) AF: 0.0816 AC: 2811 AN: 34438

South Asian (SAS) AF: 0.00402 AC: 210 AN: 52180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44484

Middle Eastern (MID) AF: 0.000358 AC: 1 AN: 2792

European-Non Finnish (NFE) AF: 0.0000554 AC: 24 AN: 433592

Other (OTH) AF: 0.00294 AC: 96 AN: 32616

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152300 Hom.: 15 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74472

African (AFR) AF: 0.000241 AC: 10 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0605 AC: 314 AN: 5188

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000516 Hom.: 3

Bravo AF: 0.00205

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.8
DANN	Benign	0.72
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

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: rs2269418; hg19: chr6-32180120;