19-15180765-C-T

Variant names:

• chr19-15180765-C-T
• rs35769976
• NM_000435.3:c.3058G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000435.3(NOTCH3):​c.3058G>A​(p.Ala1020Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,449,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1020P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• Publications: 36 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000435.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.12745768).

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.3058G>A	p.Ala1020Thr	missense	Exon 19 of 33	NP_000426.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.3058G>A	p.Ala1020Thr	missense	Exon 19 of 33	ENSP00000263388.1
	NOTCH3	ENST00000931534.1		c.3193G>A	p.Ala1065Thr	missense	Exon 20 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.2881G>A	p.Ala961Thr	missense	Exon 18 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 228302 AF XY: 0.00000810

Gnomad AFR exome AF: 0.0000711

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449920 Hom.: 0 Cov.: 34 AF XY: 0.00000417 AC XY: 3 AN XY: 720014

African (AFR) AF: 0.0000300 AC: 1 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 42694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39278

South Asian (SAS) AF: 0.00 AC: 0 AN: 83690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107116

Other (OTH) AF: 0.00 AC: 0 AN: 59972

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 22

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.12	N
PhyloP100		0.26
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.17
Sift	Benign	0.44	T
Sift4G	Benign	0.68	T
Polyphen		0.047	B
Vest4		0.15
MutPred		0.64		Gain of disorder (P = 0.0725)
MVP		0.85
MPC		0.42
ClinPred		0.058	T
GERP RS		1.4
Varity_R		0.059
gMVP		0.58
Mutation Taster		=94/6	polymorphism

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: rs35769976; hg19: chr19-15291576; COSMIC: COSV54627267;