chr6-32212654-A-T

Variant names:

• chr6-32212654-A-T
• rs2071285
• NM_004557.4:c.2527-27T>A

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.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
• Publications: 25 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=-0.88).
• BP6: Variant 6-32212654-A-T is Benign according to our data. Variant chr6-32212654-A-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2527-27T>A		intron_variant	Intron 16 of 29	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2768-27T>A		intron_variant	Intron 17 of 29
NOTCH4	NR_134950.2	n.2666-27T>A		intron_variant	Intron 16 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2527-27T>A		intron_variant	Intron 16 of 29	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000465528.1	n.400-27T>A		intron_variant	Intron 3 of 4	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

GnomAD2 exomes AF: 0.0704 AC: 15910 AN: 226040 AF XY: 0.0684

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 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

African (AFR) AF: 0.0358 AC: 1188 AN: 33146

American (AMR) AF: 0.0701 AC: 3006 AN: 42856

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3676 AN: 24280

East Asian (EAS) AF: 0.208 AC: 8250 AN: 39582

South Asian (SAS) AF: 0.0612 AC: 5048 AN: 82530

European-Finnish (FIN) AF: 0.0290 AC: 1501 AN: 51694

Middle Eastern (MID) AF: 0.0712 AC: 390 AN: 5480

European-Non Finnish (NFE) AF: 0.0668 AC: 73574 AN: 1101970

Other (OTH) AF: 0.0762 AC: 4538 AN: 59564

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

African (AFR) AF: 0.0366 AC: 1518 AN: 41494

American (AMR) AF: 0.0586 AC: 896 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3470

East Asian (EAS) AF: 0.196 AC: 1004 AN: 5112

South Asian (SAS) AF: 0.0703 AC: 338 AN: 4810

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10604

Middle Eastern (MID) AF: 0.0556 AC: 16 AN: 288

European-Non Finnish (NFE) AF: 0.0562 AC: 3820 AN: 67954

Other (OTH) AF: 0.0678 AC: 143 AN: 2108

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

May 15, 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	-0.88
CADD	Benign	3.9
DANN	Benign	0.75
PhyloP100		-0.032
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071285; hg19: chr6-32180431; COSMIC: COSV66678980; COSMIC: COSV66678980;