6-32212369-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2680+105T>C		intron_variant	Intron 17 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2921+105T>C		intron_variant	Intron 18 of 29
NOTCH4	NR_134950.2	n.2819+105T>C		intron_variant	Intron 17 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2680+105T>C		intron_variant	Intron 17 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000465528.1	n.553+105T>C		intron_variant	Intron 4 of 4	5

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

Gnomad4 AFR exome AF: 0.978

Gnomad4 AMR exome AF: 0.950

Gnomad4 ASJ exome AF: 0.970

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.976

Gnomad4 FIN exome AF: 0.860

Gnomad4 NFE exome AF: 0.858

Gnomad4 OTH exome AF: 0.890

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

Gnomad4 AFR AF: 0.973

Gnomad4 AMR AF: 0.935

Gnomad4 ASJ AF: 0.970

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.974

Gnomad4 FIN AF: 0.875

Gnomad4 NFE AF: 0.864

Gnomad4 OTH AF: 0.937

Alfa AF: 0.890 Hom.: 38335

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.4
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs3131294; hg19: chr6-32180146;