rs1555727412

Variant names:

• chr19-15177921-T-TTGC
• rs1555727412
• NM_000435.3:c.4004_4006dupGCA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PM4_Supporting

The NM_000435.3(NOTCH3):​c.4004_4006dupGCA​(p.Ser1335dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,284,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.968
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity NOTC3_HUMAN
• PM4: Nonframeshift variant in NON repetitive region in NM_000435.3. Strenght limited to Supporting due to length of the change: 1aa.

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.4004_4006dupGCA	p.Ser1335dup	conservative_inframe_insertion	Exon 24 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.4004_4006dupGCA	p.Ser1335dup	conservative_inframe_insertion	Exon 24 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.4139_4141dupGCA	p.Ser1380dup	conservative_inframe_insertion	Exon 25 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.3827_3829dupGCA	p.Ser1276dup	conservative_inframe_insertion	Exon 23 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151434 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000971 AC: 11 AN: 1133142 Hom.: 0 Cov.: 32 AF XY: 0.0000111 AC XY: 6 AN XY: 542222

African (AFR) AF: 0.00 AC: 0 AN: 22882

American (AMR) AF: 0.00 AC: 0 AN: 8378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15020

East Asian (EAS) AF: 0.00 AC: 0 AN: 26070

South Asian (SAS) AF: 0.00 AC: 0 AN: 35986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3072

European-Non Finnish (NFE) AF: 0.0000116 AC: 11 AN: 951354

Other (OTH) AF: 0.00 AC: 0 AN: 45916

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151434 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 73940

African (AFR) AF: 0.00 AC: 0 AN: 41304

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67812

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=61/39	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555727412; hg19: chr19-15288732;