rs4809030

Variant names:

• chr19-15162570-A-G
• rs4809030
• NM_000435.3:c.5816-8T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-15162570-A-G
• chr19-15162570-A-C
• chr19-15162570-A-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.5816-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 1,612,158 control chromosomes in the GnomAD database, including 644,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62118 hom., cov: 31)
  • Exomes 𝑓: 0.89 (582047 hom.)
• Consequence: NOTCH3 NM_000435.3 splice_region, intron
• Scores: Splicing: ADA: 0.000005957
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.364
• Publications: 18 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 (BayesDel_noAF=-0.88).
• BP6: Variant 19-15162570-A-G is Benign according to our data. Variant chr19-15162570-A-G is described in ClinVar as Benign. ClinVar VariationId is 256145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.966 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.5816-8T>C		splice_region intron	N/A	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.5816-8T>C		splice_region intron	N/A	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.5951-8T>C		splice_region intron	N/A	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.5639-8T>C		splice_region intron	N/A	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.901 AC: 137041 AN: 152068 Hom.: 62067 Cov.: 31

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.878

GnomAD2 exomes AF: 0.864 AC: 216238 AN: 250336 AF XY: 0.866

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.800

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.900

Gnomad OTH exome AF: 0.862

GnomAD4 exome AF: 0.892 AC: 1302111 AN: 1459972 Hom.: 582047 Cov.: 34 AF XY: 0.891 AC XY: 646816 AN XY: 726344

African (AFR) AF: 0.979 AC: 32739 AN: 33444

American (AMR) AF: 0.722 AC: 32186 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 22774 AN: 26124

East Asian (EAS) AF: 0.827 AC: 32812 AN: 39690

South Asian (SAS) AF: 0.853 AC: 73505 AN: 86152

European-Finnish (FIN) AF: 0.887 AC: 47200 AN: 53204

Middle Eastern (MID) AF: 0.847 AC: 4869 AN: 5748

European-Non Finnish (NFE) AF: 0.903 AC: 1003011 AN: 1110702

Other (OTH) AF: 0.879 AC: 53015 AN: 60322

GnomAD4 genome AF: 0.901 AC: 137150 AN: 152186 Hom.: 62118 Cov.: 31 AF XY: 0.897 AC XY: 66714 AN XY: 74396

African (AFR) AF: 0.974 AC: 40475 AN: 41542

American (AMR) AF: 0.781 AC: 11928 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3047 AN: 3472

East Asian (EAS) AF: 0.806 AC: 4148 AN: 5148

South Asian (SAS) AF: 0.851 AC: 4111 AN: 4828

European-Finnish (FIN) AF: 0.884 AC: 9357 AN: 10590

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.899 AC: 61161 AN: 68014

Other (OTH) AF: 0.879 AC: 1858 AN: 2114

Alfa AF: 0.905 Hom.: 26237

Bravo AF: 0.895

Asia WGS AF: 0.850 AC: 2956 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
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.59
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000060
dbscSNV1_RF	Benign	0.0
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: rs4809030; hg19: chr19-15273381;