6-32219828-A-G

Variant names:

• chr6-32219828-A-G
• rs1109771
• NM_004557.4:c.1316-42T>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.1316-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,541,746 control chromosomes in the GnomAD database, including 240,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (22650 hom., cov: 30)
  • Exomes 𝑓: 0.56 (217433 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.747
• Publications: 23 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=-0.9).
• BP6: Variant 6-32219828-A-G is Benign according to our data. Variant chr6-32219828-A-G is described in ClinVar as Benign. ClinVar VariationId is 1252692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 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.1316-42T>C		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.1455-42T>C		intron	N/A
	NOTCH4	NR_134950.2		n.1455-42T>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.1316-42T>C		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000473562.1	TSL:1	n.1445-42T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82499 AN: 151662 Hom.: 22650 Cov.: 30

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.552

GnomAD2 exomes AF: 0.566 AC: 114788 AN: 202632 AF XY: 0.571

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.716

Gnomad EAS exome AF: 0.678

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.562

GnomAD4 exome AF: 0.559 AC: 776426 AN: 1389966 Hom.: 217433 Cov.: 23 AF XY: 0.560 AC XY: 386834 AN XY: 690590

African (AFR) AF: 0.525 AC: 16834 AN: 32046

American (AMR) AF: 0.516 AC: 20306 AN: 39336

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 17517 AN: 24656

East Asian (EAS) AF: 0.695 AC: 26826 AN: 38592

South Asian (SAS) AF: 0.592 AC: 48048 AN: 81182

European-Finnish (FIN) AF: 0.485 AC: 24652 AN: 50832

Middle Eastern (MID) AF: 0.580 AC: 2898 AN: 4994

European-Non Finnish (NFE) AF: 0.553 AC: 586863 AN: 1060396

Other (OTH) AF: 0.561 AC: 32482 AN: 57932

GnomAD4 genome AF: 0.544 AC: 82543 AN: 151780 Hom.: 22650 Cov.: 30 AF XY: 0.541 AC XY: 40122 AN XY: 74156

African (AFR) AF: 0.519 AC: 21470 AN: 41372

American (AMR) AF: 0.519 AC: 7906 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2461 AN: 3464

East Asian (EAS) AF: 0.696 AC: 3578 AN: 5138

South Asian (SAS) AF: 0.609 AC: 2923 AN: 4800

European-Finnish (FIN) AF: 0.492 AC: 5172 AN: 10516

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.547 AC: 37140 AN: 67932

Other (OTH) AF: 0.556 AC: 1174 AN: 2112

Alfa AF: 0.553 Hom.: 34844

Bravo AF: 0.546

Asia WGS AF: 0.602 AC: 2093 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	-0.90
CADD	Benign	2.8
DANN	Benign	0.64
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1109771; hg19: chr6-32187605; COSMIC: COSV66684189;