6-32196022-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004557.4(NOTCH4):c.5427A>G(p.Gln1809=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,598,326 control chromosomes in the GnomAD database, including 2,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.062 (343 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2542 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-32196022-T-C is Benign according to our data. Variant chr6-32196022-T-C is described in ClinVar as [Benign]. Clinvar id is 1290716.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.5427A>G	p.Gln1809=	synonymous_variant	30/30	ENST00000375023.3
NOTCH4	NR_134949.2	n.5135A>G		non_coding_transcript_exon_variant	30/30
NOTCH4	NR_134950.2	n.5033A>G		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5427A>G	p.Gln1809=	synonymous_variant	30/30	1	NM_004557.4	P1
NOTCH4	ENST00000474612.1	n.4088A>G		non_coding_transcript_exon_variant	10/10	5
NOTCH4	ENST00000491215.1	n.453A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9371 AN: 152118 Hom.: 345 Cov.: 33

Gnomad AFR AF: 0.0814

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0506

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0669

GnomAD3 exomes AF: 0.0531 AC: 11572 AN: 217950 Hom.: 409 AF XY: 0.0569 AC XY: 6906 AN XY: 121402

Gnomad AFR exome AF: 0.0810

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.0365

Gnomad SAS exome AF: 0.0971

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.0557

GnomAD4 exome AF: 0.0562 AC: 81251 AN: 1446090 Hom.: 2542 Cov.: 32 AF XY: 0.0571 AC XY: 41073 AN XY: 719706

Gnomad4 AFR exome AF: 0.0893

Gnomad4 AMR exome AF: 0.0346

Gnomad4 ASJ exome AF: 0.0496

Gnomad4 EAS exome AF: 0.0539

Gnomad4 SAS exome AF: 0.0934

Gnomad4 FIN exome AF: 0.0212

Gnomad4 NFE exome AF: 0.0544

Gnomad4 OTH exome AF: 0.0593

GnomAD4 genome AF: 0.0615 AC: 9369 AN: 152236 Hom.: 343 Cov.: 33 AF XY: 0.0604 AC XY: 4499 AN XY: 74436

Gnomad4 AFR AF: 0.0812

Gnomad4 AMR AF: 0.0505

Gnomad4 ASJ AF: 0.0456

Gnomad4 EAS AF: 0.0468

Gnomad4 SAS AF: 0.0989

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0566

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0424 Hom.: 56

Bravo AF: 0.0648

Asia WGS AF: 0.0690 AC: 240 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 05, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	9.1
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8192579; hg19: chr6-32163799; COSMIC: COSV66678923; COSMIC: COSV66678923;