rs2071285

chr6-32212654-A-T

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.2527-27T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,593,128 control chromosomes in the GnomAD database, including 4,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (338 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4231 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0320

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=-0.88).
• BP6: Variant 6-32212654-A-T is Benign according to our data. Variant chr6-32212654-A-T is described in ClinVar as [Benign]. Clinvar id is 1246003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.2527-27T>A		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.2768-27T>A		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.2666-27T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2527-27T>A		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000465528.1	n.400-27T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8568 AN: 151910 Hom.: 335 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.0484

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0657

GnomAD3 exomes AF: 0.0704 AC: 15910 AN: 226040 Hom.: 717 AF XY: 0.0684 AC XY: 8353 AN XY: 122180

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.0725

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.0617

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0592

Gnomad OTH exome AF: 0.0755

GnomAD4 exome AF: 0.0702 AC: 101171 AN: 1441102 Hom.: 4231 Cov.: 32 AF XY: 0.0696 AC XY: 49770 AN XY: 715280

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.0701

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.0612

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0668

Gnomad4 OTH exome AF: 0.0762

GnomAD4 genome AF: 0.0564 AC: 8580 AN: 152026 Hom.: 338 Cov.: 32 AF XY: 0.0559 AC XY: 4157 AN XY: 74310

Gnomad4 AFR AF: 0.0366

Gnomad4 AMR AF: 0.0586

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.0703

Gnomad4 FIN AF: 0.0275

Gnomad4 NFE AF: 0.0562

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0658 Hom.: 90

Bravo AF: 0.0597

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	3.9
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2071285; hg19: chr6-32180431; COSMIC: COSV66678980; COSMIC: COSV66678980;