19-15159945-G-C

Variant names:

• chr19-15159945-G-C
• rs3087938
• NM_000435.3:c.*717C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000435.3(NOTCH3):​c.*717C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 233,712 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.97
• Publications: 0 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.*717C>G		3_prime_UTR	Exon 33 of 33	NP_000426.2	Q9UM47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.*717C>G		3_prime_UTR	Exon 33 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.*717C>G		3_prime_UTR	Exon 34 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.*717C>G		3_prime_UTR	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000503 AC: 41 AN: 81460 Hom.: 0 Cov.: 0 AF XY: 0.000586 AC XY: 22 AN XY: 37536

African (AFR) AF: 0.00 AC: 0 AN: 3894

American (AMR) AF: 0.00120 AC: 3 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.000782 AC: 4 AN: 5112

East Asian (EAS) AF: 0.00 AC: 0 AN: 11416

South Asian (SAS) AF: 0.00 AC: 0 AN: 704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 492

Middle Eastern (MID) AF: 0.00810 AC: 4 AN: 494

European-Non Finnish (NFE) AF: 0.000559 AC: 28 AN: 50074

Other (OTH) AF: 0.000295 AC: 2 AN: 6776

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152252 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000261

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.53
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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: rs3087938; hg19: chr19-15270756;