rs147373451

Variant names:

• chr19-15192130-T-C
• rs147373451
• NM_000435.3:c.509A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-15192130-T-C
• chr19-15192130-T-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000435.3(NOTCH3):​c.509A>G​(p.His170Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,612,974 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (11 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.11
• Publications: 32 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 -14 ACMG points.

• PM1: In a hotspot region, there are 14 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=0.014457643).
• BP6: Variant 19-15192130-T-C is Benign according to our data. Variant chr19-15192130-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.509A>G	p.His170Arg	missense	Exon 4 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.509A>G	p.His170Arg	missense	Exon 4 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.509A>G	p.His170Arg	missense	Exon 4 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.488A>G	p.His163Arg	missense	Exon 4 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00184 AC: 457 AN: 248134 AF XY: 0.00212

Gnomad AFR exome AF: 0.000629

Gnomad AMR exome AF: 0.000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.00303 AC: 4422 AN: 1460714 Hom.: 11 Cov.: 40 AF XY: 0.00309 AC XY: 2244 AN XY: 726688

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.000693 AC: 31 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00424 AC: 366 AN: 86258

European-Finnish (FIN) AF: 0.0000956 AC: 5 AN: 52296

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00339 AC: 3766 AN: 1111994

Other (OTH) AF: 0.00374 AC: 226 AN: 60384

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74446

African (AFR) AF: 0.000626 AC: 26 AN: 41560

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00156

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (3)
-	-	1	Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)
-	-	1	not specified (1)
-	-	1	NOTCH3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.97	D
Vest4		0.82
MVP		0.94
MPC		0.93
ClinPred		0.049	T
GERP RS		4.9
Varity_R		0.44
gMVP		0.51
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147373451; hg19: chr19-15302941;