rs114447350

Variant names:

• chr19-15161407-G-A
• rs114447350
• NM_000435.3:c.6221C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-15161407-G-A
• chr19-15161407-G-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.6221C>T​(p.Pro2074Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00476 in 1,525,304 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2074Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (148 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (139 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.61
• Publications: 9 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 (MetaRNN=0.001966834).
• BP6: Variant 19-15161407-G-A is Benign according to our data. Variant chr19-15161407-G-A is described in ClinVar as Benign. ClinVar VariationId is 256150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 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.6221C>T	p.Pro2074Leu	missense	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.6221C>T	p.Pro2074Leu	missense	Exon 33 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.6356C>T	p.Pro2119Leu	missense	Exon 34 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.6044C>T	p.Pro2015Leu	missense	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3761 AN: 152082 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00563 AC: 702 AN: 124650 AF XY: 0.00415

Gnomad AFR exome AF: 0.0935

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00254 AC: 3485 AN: 1373104 Hom.: 139 Cov.: 36 AF XY: 0.00221 AC XY: 1491 AN XY: 675262

African (AFR) AF: 0.0918 AC: 2816 AN: 30666

American (AMR) AF: 0.00425 AC: 136 AN: 32008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23960

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35520

South Asian (SAS) AF: 0.000142 AC: 11 AN: 77264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43668

Middle Eastern (MID) AF: 0.00325 AC: 16 AN: 4924

European-Non Finnish (NFE) AF: 0.000171 AC: 183 AN: 1068474

Other (OTH) AF: 0.00569 AC: 322 AN: 56620

GnomAD4 genome AF: 0.0248 AC: 3778 AN: 152200 Hom.: 148 Cov.: 32 AF XY: 0.0238 AC XY: 1773 AN XY: 74406

African (AFR) AF: 0.0868 AC: 3606 AN: 41530

American (AMR) AF: 0.00732 AC: 112 AN: 15294

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67990

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00850 Hom.: 15

Bravo AF: 0.0289

ESP6500AA AF: 0.0483 AC: 128

ESP6500EA AF: 0.000332 AC: 2

ExAC AF: 0.00251 AC: 240

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)
-	-	1	Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.28	T
Polyphen		0.051	B
Vest4		0.15
MVP		0.90
MPC		0.57
ClinPred		0.0081	T
GERP RS		3.8
Varity_R		0.086
gMVP		0.55
Mutation Taster		=90/10	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: rs114447350; hg19: chr19-15272218; COSMIC: COSV54633767; COSMIC: COSV54633767;