rs11670799

Variant names:

• chr19-15188240-G-A
• rs11670799
• NM_000435.3:c.1487C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000435.3(NOTCH3):​c.1487C>T​(p.Pro496Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0157 in 1,596,008 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P496P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 32)
  • Exomes 𝑓: 0.016 (264 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.84
• Publications: 25 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 -18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in NM_000435.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056042075).
• BP6: Variant 19-15188240-G-A is Benign according to our data. Variant chr19-15188240-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1862/152256) while in subpopulation NFE AF = 0.0169 (1150/68004). AF 95% confidence interval is 0.0161. There are 24 homozygotes in GnomAd4. There are 849 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

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.1487C>T	p.Pro496Leu	missense	Exon 9 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.1487C>T	p.Pro496Leu	missense	Exon 9 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.1487C>T	p.Pro496Leu	missense	Exon 9 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.1466C>T	p.Pro489Leu	missense	Exon 9 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1862 AN: 152138 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00377

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0122 AC: 2765 AN: 226228 AF XY: 0.0124

Gnomad AFR exome AF: 0.00292

Gnomad AMR exome AF: 0.00953

Gnomad ASJ exome AF: 0.0560

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0161 AC: 23232 AN: 1443752 Hom.: 264 Cov.: 31 AF XY: 0.0158 AC XY: 11339 AN XY: 716594

African (AFR) AF: 0.00250 AC: 83 AN: 33244

American (AMR) AF: 0.00985 AC: 421 AN: 42724

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 1528 AN: 25708

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39298

South Asian (SAS) AF: 0.00160 AC: 134 AN: 83536

European-Finnish (FIN) AF: 0.00361 AC: 187 AN: 51826

Middle Eastern (MID) AF: 0.00765 AC: 44 AN: 5748

European-Non Finnish (NFE) AF: 0.0180 AC: 19830 AN: 1102016

Other (OTH) AF: 0.0168 AC: 1002 AN: 59652

GnomAD4 genome AF: 0.0122 AC: 1862 AN: 152256 Hom.: 24 Cov.: 32 AF XY: 0.0114 AC XY: 849 AN XY: 74450

African (AFR) AF: 0.00375 AC: 156 AN: 41550

American (AMR) AF: 0.0147 AC: 225 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 203 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1150 AN: 68004

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0162 Hom.: 64

Bravo AF: 0.0136

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0215 AC: 185

ExAC AF: 0.0101 AC: 1220

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)
-	-	1	Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.34
MPC		1.0
ClinPred		0.043	T
GERP RS		5.0
Varity_R		0.30
gMVP		0.77
Mutation Taster		=88/12	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: rs11670799; hg19: chr19-15299051;