chr19-15172784-G-C

Variant names:

• chr19-15172784-G-C
• rs10426843
• NM_000435.3:c.4736+1284C>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.4736+1284C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 150,944 control chromosomes in the GnomAD database, including 61,550 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 0.90 (61550 hom., cov: 25)
• Consequence: NOTCH3 NM_000435.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.377
• Publications: 1 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.4736+1284C>G		intron_variant	Intron 25 of 32	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.4580+1284C>G		intron_variant	Intron 24 of 31		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.4736+1284C>G		intron_variant	Intron 25 of 32	1	NM_000435.3	ENSP00000263388.1

Frequencies

GnomAD3 genomes AF: 0.901 AC: 135865 AN: 150828 Hom.: 61504 Cov.: 25

Gnomad AFR AF: 0.973

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.880

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

GnomAD4 genome AF: 0.901 AC: 135968 AN: 150944 Hom.: 61550 Cov.: 25 AF XY: 0.897 AC XY: 66041 AN XY: 73664

African (AFR) AF: 0.973 AC: 40047 AN: 41168

American (AMR) AF: 0.782 AC: 11824 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 3026 AN: 3456

East Asian (EAS) AF: 0.805 AC: 4073 AN: 5062

South Asian (SAS) AF: 0.849 AC: 4052 AN: 4770

European-Finnish (FIN) AF: 0.883 AC: 9131 AN: 10336

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.899 AC: 60912 AN: 67736

Other (OTH) AF: 0.880 AC: 1840 AN: 2090

Alfa AF: 0.880 Hom.: 2852

Bravo AF: 0.895

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.9
DANN	Benign	0.80
PhyloP100		0.38
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: rs10426843; hg19: chr19-15283595;