6-32212369-A-G

Variant names:

• chr6-32212369-A-G
• rs3131294
• NM_004557.4:c.2680+105T>C

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.2680+105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,036,354 control chromosomes in the GnomAD database, including 408,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.91 (63777 hom., cov: 33)
  • Exomes 𝑓: 0.88 (344872 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51
• Publications: 46 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=-0.91).
• BP6: Variant 6-32212369-A-G is Benign according to our data. Variant chr6-32212369-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250163.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 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.2680+105T>C		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.2921+105T>C		intron	N/A
	NOTCH4	NR_134950.2		n.2819+105T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.2680+105T>C		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000465528.1	TSL:5	n.553+105T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139015 AN: 152160 Hom.: 63714 Cov.: 33

Gnomad AFR AF: 0.973

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.974

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.936

GnomAD4 exome AF: 0.881 AC: 779193 AN: 884076 Hom.: 344872 AF XY: 0.885 AC XY: 397058 AN XY: 448410

African (AFR) AF: 0.978 AC: 20393 AN: 20858

American (AMR) AF: 0.950 AC: 24409 AN: 25690

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 16196 AN: 16698

East Asian (EAS) AF: 0.999 AC: 35901 AN: 35950

South Asian (SAS) AF: 0.976 AC: 57733 AN: 59150

European-Finnish (FIN) AF: 0.860 AC: 40684 AN: 47286

Middle Eastern (MID) AF: 0.940 AC: 3462 AN: 3684

European-Non Finnish (NFE) AF: 0.858 AC: 544566 AN: 634468

Other (OTH) AF: 0.890 AC: 35849 AN: 40292

GnomAD4 genome AF: 0.914 AC: 139136 AN: 152278 Hom.: 63777 Cov.: 33 AF XY: 0.915 AC XY: 68131 AN XY: 74452

African (AFR) AF: 0.973 AC: 40449 AN: 41560

American (AMR) AF: 0.935 AC: 14293 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 3369 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5154 AN: 5178

South Asian (SAS) AF: 0.974 AC: 4703 AN: 4830

European-Finnish (FIN) AF: 0.875 AC: 9280 AN: 10608

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58784 AN: 68020

Other (OTH) AF: 0.937 AC: 1979 AN: 2112

Alfa AF: 0.890 Hom.: 152839

Bravo AF: 0.921

Asia WGS AF: 0.981 AC: 3413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.4
DANN	Benign	0.77
PhyloP100		-1.5
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: rs3131294; hg19: chr6-32180146;