NM_000435.3:c.3058G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.3058G>C​(p.Ala1020Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,602,146 control chromosomes in the GnomAD database, including 3,918 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (1991 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1927 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:11
• 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: Benign. The variant received -18 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=0.005243212).
• BP6: Variant 19-15180765-C-G is Benign according to our data. Variant chr19-15180765-C-G is described in ClinVar as Benign. ClinVar VariationId is 9227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 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.3058G>C	p.Ala1020Pro	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>C	p.Ala1020Pro	missense	Exon 19 of 33	ENSP00000263388.1
	NOTCH3	ENST00000931534.1		c.3193G>C	p.Ala1065Pro	missense	Exon 20 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.2881G>C	p.Ala961Pro	missense	Exon 18 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0981 AC: 14929 AN: 152138 Hom.: 1982 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0779

GnomAD2 exomes AF: 0.0351 AC: 8005 AN: 228302 AF XY: 0.0310

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.000581

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0201 AC: 29164 AN: 1449890 Hom.: 1927 Cov.: 34 AF XY: 0.0196 AC XY: 14127 AN XY: 719994

African (AFR) AF: 0.312 AC: 10407 AN: 33316

American (AMR) AF: 0.0262 AC: 1119 AN: 42690

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 901 AN: 25794

East Asian (EAS) AF: 0.000356 AC: 14 AN: 39278

South Asian (SAS) AF: 0.0283 AC: 2372 AN: 83684

European-Finnish (FIN) AF: 0.0153 AC: 801 AN: 52292

Middle Eastern (MID) AF: 0.0440 AC: 253 AN: 5754

European-Non Finnish (NFE) AF: 0.0101 AC: 11209 AN: 1107110

Other (OTH) AF: 0.0348 AC: 2088 AN: 59972

GnomAD4 genome AF: 0.0982 AC: 14959 AN: 152256 Hom.: 1991 Cov.: 32 AF XY: 0.0951 AC XY: 7082 AN XY: 74448

African (AFR) AF: 0.307 AC: 12754 AN: 41500

American (AMR) AF: 0.0450 AC: 689 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4828

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 801 AN: 68032

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

Alfa AF: 0.0147 Hom.: 22

Bravo AF: 0.110

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.294 AC: 1294

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.0384 AC: 4652

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
1	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (2)
-	-	2	Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	N
PhyloP100		0.26
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.30	T
Polyphen		0.027	B
Vest4		0.22
MPC		0.57
ClinPred		0.0082	T
GERP RS		1.4
Varity_R		0.22
gMVP		0.85
Mutation Taster		=98/2	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: rs35769976; hg19: chr19-15291576; COSMIC: COSV54631885; COSMIC: COSV54631885;