rs150079294

Positions:

• chr6-32212907-A-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_004557.4(NOTCH4):​c.2443T>G​(p.Cys815Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00436 in 1,563,840 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (29 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.55

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 -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.030241013).
• BP6: Variant 6-32212907-A-C is Benign according to our data. Variant chr6-32212907-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 221935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 598 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2443T>G	p.Cys815Gly	missense_variant	16/30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.2684T>G		non_coding_transcript_exon_variant	17/30
NOTCH4	NR_134950.2	n.2582T>G		non_coding_transcript_exon_variant	16/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2443T>G	p.Cys815Gly	missense_variant	16/30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000465528.1	n.399+228T>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152104 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00337 AC: 574 AN: 170274 Hom.: 2 AF XY: 0.00301 AC XY: 275 AN XY: 91296

Gnomad AFR exome AF: 0.000748

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000989

Gnomad NFE exome AF: 0.00485

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00441 AC: 6224 AN: 1411618 Hom.: 29 Cov.: 31 AF XY: 0.00415 AC XY: 2893 AN XY: 697864

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00808

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000938

Gnomad4 NFE exome AF: 0.00519

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152222 Hom.: 4 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74460

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00405 Hom.: 1

Bravo AF: 0.00518

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000669 AC: 2

ESP6500EA AF: 0.00372 AC: 20

ExAC AF: 0.00163 AC: 192

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2018

- -

Anophthalmia-microphthalmia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.030	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.99
MPC		0.63
ClinPred		0.13	T
GERP RS		4.2
Varity_R		0.45
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150079294; hg19: chr6-32180684;