19-15159825-C-T

Variant names:

• chr19-15159825-C-T
• rs12082
• NM_000435.3:c.*837G>A

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.*837G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 233,650 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (75 hom., cov: 35)
  • Exomes 𝑓: 0.034 (62 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.18
• Publications: 7 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, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• 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=-0.88).
• BP6: Variant 19-15159825-C-T is Benign according to our data. Variant chr19-15159825-C-T is described in ClinVar as Benign. ClinVar VariationId is 328359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0867 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.*837G>A		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.*837G>A		3_prime_UTR	Exon 33 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.*837G>A		3_prime_UTR	Exon 34 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.*837G>A		3_prime_UTR	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3372 AN: 152258 Hom.: 75 Cov.: 35

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0932

Gnomad SAS AF: 0.0525

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.0337 AC: 2739 AN: 81274 Hom.: 62 Cov.: 0 AF XY: 0.0343 AC XY: 1284 AN XY: 37448

African (AFR) AF: 0.00541 AC: 21 AN: 3882

American (AMR) AF: 0.0176 AC: 44 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.00939 AC: 48 AN: 5110

East Asian (EAS) AF: 0.0804 AC: 916 AN: 11400

South Asian (SAS) AF: 0.0370 AC: 26 AN: 702

European-Finnish (FIN) AF: 0.00617 AC: 3 AN: 486

Middle Eastern (MID) AF: 0.0305 AC: 15 AN: 492

European-Non Finnish (NFE) AF: 0.0295 AC: 1472 AN: 49956

Other (OTH) AF: 0.0287 AC: 194 AN: 6752

GnomAD4 genome AF: 0.0221 AC: 3367 AN: 152376 Hom.: 75 Cov.: 35 AF XY: 0.0224 AC XY: 1670 AN XY: 74506

African (AFR) AF: 0.00608 AC: 253 AN: 41598

American (AMR) AF: 0.0144 AC: 220 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.0936 AC: 485 AN: 5180

South Asian (SAS) AF: 0.0519 AC: 251 AN: 4834

European-Finnish (FIN) AF: 0.0140 AC: 149 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1923 AN: 68036

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0268 Hom.: 186

Bravo AF: 0.0216

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.88
CADD	Benign	2.8
DANN	Benign	0.48
PhyloP100		1.2
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: rs12082; hg19: chr19-15270636;