19-15159994-C-A

Variant names:

• chr19-15159994-C-A
• rs1044055
• NM_000435.3:c.*668G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.*668G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 233,276 control chromosomes in the GnomAD database, including 57,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36415 hom., cov: 33)
  • Exomes 𝑓: 0.72 (21184 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.336
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-15159994-C-A is Benign according to our data. Variant chr19-15159994-C-A is described in ClinVar as Benign. ClinVar VariationId is 328361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.767 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.*668G>T		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.*668G>T		3_prime_UTR	Exon 33 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.*668G>T		3_prime_UTR	Exon 34 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.*668G>T		3_prime_UTR	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103901 AN: 152030 Hom.: 36406 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.683

GnomAD4 exome AF: 0.718 AC: 58243 AN: 81128 Hom.: 21184 Cov.: 0 AF XY: 0.723 AC XY: 27008 AN XY: 37348

African (AFR) AF: 0.520 AC: 2012 AN: 3868

American (AMR) AF: 0.589 AC: 1465 AN: 2486

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 3752 AN: 5090

East Asian (EAS) AF: 0.609 AC: 6919 AN: 11364

South Asian (SAS) AF: 0.743 AC: 523 AN: 704

European-Finnish (FIN) AF: 0.796 AC: 401 AN: 504

Middle Eastern (MID) AF: 0.672 AC: 328 AN: 488

European-Non Finnish (NFE) AF: 0.765 AC: 38138 AN: 49874

Other (OTH) AF: 0.697 AC: 4705 AN: 6750

GnomAD4 genome AF: 0.683 AC: 103936 AN: 152148 Hom.: 36415 Cov.: 33 AF XY: 0.683 AC XY: 50810 AN XY: 74378

African (AFR) AF: 0.533 AC: 22124 AN: 41490

American (AMR) AF: 0.616 AC: 9416 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2520 AN: 3470

East Asian (EAS) AF: 0.578 AC: 2972 AN: 5142

South Asian (SAS) AF: 0.722 AC: 3487 AN: 4832

European-Finnish (FIN) AF: 0.806 AC: 8541 AN: 10602

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.772 AC: 52505 AN: 67994

Other (OTH) AF: 0.684 AC: 1447 AN: 2114

Alfa AF: 0.668 Hom.: 2363

Bravo AF: 0.659

Asia WGS AF: 0.637 AC: 2218 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.3
DANN	Benign	0.82
PhyloP100		0.34
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: rs1044055; hg19: chr19-15270805; COSMIC: COSV54630515; COSMIC: COSV54630515;