rs748339634

chr19-15192207-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000435.3(NOTCH3):c.432C>T(p.Cys144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,611,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.865

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-15192207-G-A is Benign according to our data. Variant chr19-15192207-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15192207-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.865 with no splicing effect.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.432C>T	p.Cys144=	synonymous_variant	4/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.432C>T	p.Cys144=	synonymous_variant	4/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.432C>T	p.Cys144=	synonymous_variant	4/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.429C>T	p.Cys143=	synonymous_variant	4/23	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000456 AC: 11 AN: 241292 Hom.: 0 AF XY: 0.0000455 AC XY: 6 AN XY: 131826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1458864 Hom.: 0 Cov.: 39 AF XY: 0.0000262 AC XY: 19 AN XY: 725716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 11, 2018	- -

Stroke disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jun 13, 2022

ACMG categories: BP4,BP6,BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	11
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs748339634; hg19: chr19-15303018;