19-15163959-G-C

Variant names:

• chr19-15163959-G-C
• rs10426042
• NM_000435.3:c.5816-1397C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000435.3(NOTCH3):​c.5816-1397C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,170 control chromosomes in the GnomAD database, including 2,945 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2945 hom., cov: 33)
• Consequence: NOTCH3 NM_000435.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328
• Publications: 3 publications found

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]

NOTCH3 Gene-Disease associations (from GenCC):

• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myofibromatosis, infantile, 2

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000435.3. 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
	NOTCH3	NM_000435.3	MANE Select	c.5816-1397C>G		intron	N/A	NP_000426.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.5816-1397C>G		intron	N/A	ENSP00000263388.1
	NOTCH3	ENST00000597756.1	TSL:2	c.329-1397C>G		intron	N/A	ENSP00000468879.1
	NOTCH3	ENST00000595514.1	TSL:3	n.*24-1397C>G		intron	N/A	ENSP00000470661.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27085 AN: 152052 Hom.: 2933 Cov.: 33

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0777

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 27126 AN: 152170 Hom.: 2945 Cov.: 33 AF XY: 0.175 AC XY: 13047 AN XY: 74420

African (AFR) AF: 0.304 AC: 12627 AN: 41482

American (AMR) AF: 0.155 AC: 2364 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1144 AN: 5176

South Asian (SAS) AF: 0.124 AC: 599 AN: 4828

European-Finnish (FIN) AF: 0.0777 AC: 824 AN: 10604

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8553 AN: 68004

Other (OTH) AF: 0.167 AC: 351 AN: 2106

Alfa AF: 0.0616 Hom.: 66

Bravo AF: 0.191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.39
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10426042; hg19: chr19-15274770;