NM_000435.3:c.2742A>G

Variant names:

• chr19-15181626-T-C
• rs1043997
• NM_000435.3:c.2742A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000435.3(NOTCH3):​c.2742A>G​(p.Pro914Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.845 in 1,551,032 control chromosomes in the GnomAD database, including 557,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46354 hom., cov: 34)
  • Exomes 𝑓: 0.85 (510821 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -9.66
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-15181626-T-C is Benign according to our data. Variant chr19-15181626-T-C is described in ClinVar as Benign. ClinVar VariationId is 256130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.858 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.2742A>G	p.Pro914Pro	synonymous	Exon 17 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.2742A>G	p.Pro914Pro	synonymous	Exon 17 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.2877A>G	p.Pro959Pro	synonymous	Exon 18 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.2565A>G	p.Pro855Pro	synonymous	Exon 16 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117486 AN: 152050 Hom.: 46335 Cov.: 34

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.771

GnomAD2 exomes AF: 0.803 AC: 124202 AN: 154616 AF XY: 0.809

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.685

Gnomad ASJ exome AF: 0.834

Gnomad EAS exome AF: 0.810

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.804

GnomAD4 exome AF: 0.853 AC: 1192826 AN: 1398864 Hom.: 510821 Cov.: 68 AF XY: 0.852 AC XY: 587831 AN XY: 690034

African (AFR) AF: 0.600 AC: 18985 AN: 31622

American (AMR) AF: 0.689 AC: 24598 AN: 35726

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 21019 AN: 25170

East Asian (EAS) AF: 0.850 AC: 30400 AN: 35758

South Asian (SAS) AF: 0.807 AC: 63968 AN: 79262

European-Finnish (FIN) AF: 0.849 AC: 41196 AN: 48542

Middle Eastern (MID) AF: 0.784 AC: 4467 AN: 5696

European-Non Finnish (NFE) AF: 0.872 AC: 940579 AN: 1079076

Other (OTH) AF: 0.821 AC: 47614 AN: 58012

GnomAD4 genome AF: 0.772 AC: 117547 AN: 152168 Hom.: 46354 Cov.: 34 AF XY: 0.772 AC XY: 57409 AN XY: 74394

African (AFR) AF: 0.606 AC: 25150 AN: 41502

American (AMR) AF: 0.723 AC: 11060 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2916 AN: 3472

East Asian (EAS) AF: 0.826 AC: 4262 AN: 5162

South Asian (SAS) AF: 0.804 AC: 3884 AN: 4830

European-Finnish (FIN) AF: 0.846 AC: 8965 AN: 10596

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58766 AN: 67998

Other (OTH) AF: 0.771 AC: 1629 AN: 2114

Alfa AF: 0.822 Hom.: 27229

Bravo AF: 0.756

Asia WGS AF: 0.798 AC: 2772 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.014
DANN	Benign	0.28
PhyloP100		-9.7
Mutation Taster		=76/24	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: rs1043997; hg19: chr19-15292437; COSMIC: COSV54638490; COSMIC: COSV54638490;