chr6-32212907-A-C

Variant names:

• chr6-32212907-A-C
• rs150079294
• NM_004557.4:c.2443T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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 -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, 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 Benign/Likely_benign. ClinVar VariationId is 221935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 598 AD gene.

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.2443T>G	p.Cys815Gly	missense	Exon 16 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.2684T>G		non_coding_transcript_exon	Exon 17 of 30
	NOTCH4	NR_134950.2		n.2582T>G		non_coding_transcript_exon	Exon 16 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.2443T>G	p.Cys815Gly	missense	Exon 16 of 30	ENSP00000364163.3
	NOTCH4	ENST00000465528.1	TSL:5	n.399+228T>G		intron	N/A

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

GnomAD2 exomes AF: 0.00337 AC: 574 AN: 170274 AF XY: 0.00301

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 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

African (AFR) AF: 0.000896 AC: 29 AN: 32366

American (AMR) AF: 0.00808 AC: 294 AN: 36388

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25084

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37112

South Asian (SAS) AF: 0.00 AC: 0 AN: 80702

European-Finnish (FIN) AF: 0.000938 AC: 47 AN: 50088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00519 AC: 5633 AN: 1085600

Other (OTH) AF: 0.00374 AC: 219 AN: 58576

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

African (AFR) AF: 0.000915 AC: 38 AN: 41542

American (AMR) AF: 0.0141 AC: 215 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00473 AC: 322 AN: 68008

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00407 Hom.: 7

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

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Anophthalmia-microphthalmia syndrome Benign:1

Jan 01, 2013

Paul Sabatier University EA-4555, Paul Sabatier University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.6
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
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs150079294; hg19: chr6-32180684; COSMIC: COSV107496120;