19-15163959-G-C

Position:

• chr19-15163959-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.5816-1397C>G		intron_variant		ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.5660-1397C>G		intron_variant			XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.5816-1397C>G		intron_variant		1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000597756.1	c.330-1397C>G		intron_variant		2		ENSP00000468879
NOTCH3	ENST00000595514.1	c.*24-1397C>G		intron_variant, NMD_transcript_variant		3		ENSP00000470661

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

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0777

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.167

Alfa AF: 0.0616 Hom.: 66

Bravo AF: 0.191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.39

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: rs10426042; hg19: chr19-15274770;