rs1044009

Variant names:

• chr19-15160960-G-A
• rs1044009
• NM_000435.3:c.6668C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-15160960-G-A
• chr19-15160960-G-C
• chr19-15160960-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.6668C>T​(p.Ala2223Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 1,578,678 control chromosomes in the GnomAD database, including 454,095 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A2223A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.69 (37448 hom., cov: 33)
  • Exomes 𝑓: 0.76 (416647 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.20
• Publications: 76 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.551242E-7).
• BP6: Variant 19-15160960-G-A is Benign according to our data. Variant chr19-15160960-G-A is described in ClinVar as Benign. ClinVar VariationId is 256152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.78 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.6668C>T	p.Ala2223Val	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.6668C>T	p.Ala2223Val	missense	Exon 33 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.6803C>T	p.Ala2268Val	missense	Exon 34 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.6491C>T	p.Ala2164Val	missense	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105221 AN: 152020 Hom.: 37441 Cov.: 33

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.815

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.690

GnomAD2 exomes AF: 0.714 AC: 140885 AN: 197286 AF XY: 0.723

Gnomad AFR exome AF: 0.537

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.767

Gnomad EAS exome AF: 0.585

Gnomad FIN exome AF: 0.812

Gnomad NFE exome AF: 0.789

Gnomad OTH exome AF: 0.714

GnomAD4 exome AF: 0.761 AC: 1085335 AN: 1426538 Hom.: 416647 Cov.: 51 AF XY: 0.761 AC XY: 537517 AN XY: 706594

African (AFR) AF: 0.514 AC: 16886 AN: 32832

American (AMR) AF: 0.560 AC: 22158 AN: 39576

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 19198 AN: 25242

East Asian (EAS) AF: 0.601 AC: 22915 AN: 38112

South Asian (SAS) AF: 0.713 AC: 59535 AN: 83450

European-Finnish (FIN) AF: 0.811 AC: 38814 AN: 47830

Middle Eastern (MID) AF: 0.677 AC: 3848 AN: 5688

European-Non Finnish (NFE) AF: 0.785 AC: 859252 AN: 1094844

Other (OTH) AF: 0.725 AC: 42729 AN: 58964

GnomAD4 genome AF: 0.692 AC: 105253 AN: 152140 Hom.: 37448 Cov.: 33 AF XY: 0.691 AC XY: 51364 AN XY: 74364

African (AFR) AF: 0.535 AC: 22199 AN: 41494

American (AMR) AF: 0.621 AC: 9502 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2604 AN: 3470

East Asian (EAS) AF: 0.583 AC: 2995 AN: 5140

South Asian (SAS) AF: 0.723 AC: 3489 AN: 4826

European-Finnish (FIN) AF: 0.815 AC: 8644 AN: 10610

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.785 AC: 53380 AN: 67986

Other (OTH) AF: 0.692 AC: 1461 AN: 2112

Alfa AF: 0.749 Hom.: 88506

Bravo AF: 0.667

TwinsUK AF: 0.776 AC: 2879

ALSPAC AF: 0.786 AC: 3030

ESP6500AA AF: 0.603 AC: 2506

ESP6500EA AF: 0.801 AC: 6617

ExAC AF: 0.694 AC: 81542

Asia WGS AF: 0.639 AC: 2225 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (2)
-	-	1	Lateral meningocele syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.037
MPC		0.56
ClinPred		0.0050	T
GERP RS		0.43
Varity_R		0.063
gMVP		0.24
Mutation Taster		=96/4	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: rs1044009; hg19: chr19-15271771; COSMIC: COSV54625824; COSMIC: COSV54625824;