19-15177737-C-T

Variant names:

• chr19-15177737-C-T
• rs886038299
• NM_000435.3:c.4191G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_000435.3(NOTCH3):​c.4191G>A​(p.Gly1397Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,496,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1397G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.323
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=-0.323 with no splicing effect.

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.4191G>A	p.Gly1397Gly	synonymous	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.4191G>A	p.Gly1397Gly	synonymous	Exon 24 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.4326G>A	p.Gly1442Gly	synonymous	Exon 25 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.4014G>A	p.Gly1338Gly	synonymous	Exon 23 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151796 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000105 AC: 1 AN: 95138 AF XY: 0.0000187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000818 AC: 11 AN: 1345154 Hom.: 0 Cov.: 33 AF XY: 0.00000755 AC XY: 5 AN XY: 662482

African (AFR) AF: 0.000144 AC: 4 AN: 27782

American (AMR) AF: 0.00 AC: 0 AN: 31230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23724

East Asian (EAS) AF: 0.00 AC: 0 AN: 31992

South Asian (SAS) AF: 0.00 AC: 0 AN: 74878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.00000659 AC: 7 AN: 1062418

Other (OTH) AF: 0.00 AC: 0 AN: 55936

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151796 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74162

African (AFR) AF: 0.0000725 AC: 3 AN: 41398

American (AMR) AF: 0.0000656 AC: 1 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67910

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.97
PhyloP100		-0.32

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: rs886038299; hg19: chr19-15288548;