rs78926093

Variant names:

• chr19-15177884-G-A
• rs78926093
• NM_000435.3:c.4044C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-15177884-G-A
• chr19-15177884-G-C
• chr19-15177884-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000435.3(NOTCH3):​c.4044C>T​(p.Gly1348Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,240,736 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.199
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-15177884-G-A is Benign according to our data. Variant chr19-15177884-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256135.
• BP7: Synonymous conserved (PhyloP=0.199 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00742 (1124/151438) while in subpopulation AFR AF = 0.0193 (799/41462). AF 95% confidence interval is 0.0182. There are 6 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.4044C>T	p.Gly1348Gly	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.4044C>T	p.Gly1348Gly	synonymous	Exon 24 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.4179C>T	p.Gly1393Gly	synonymous	Exon 25 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.3867C>T	p.Gly1289Gly	synonymous	Exon 23 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1119 AN: 151328 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00606

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000977

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00818

GnomAD2 exomes AF: 0.00 AC: 0 AN: 78 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00228 AC: 2482 AN: 1089298 Hom.: 11 Cov.: 32 AF XY: 0.00226 AC XY: 1167 AN XY: 516988

African (AFR) AF: 0.0205 AC: 457 AN: 22308

American (AMR) AF: 0.00658 AC: 52 AN: 7898

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 184 AN: 13964

East Asian (EAS) AF: 0.00 AC: 0 AN: 25054

South Asian (SAS) AF: 0.000443 AC: 11 AN: 24848

European-Finnish (FIN) AF: 0.000544 AC: 12 AN: 22050

Middle Eastern (MID) AF: 0.00867 AC: 25 AN: 2884

European-Non Finnish (NFE) AF: 0.00167 AC: 1548 AN: 926662

Other (OTH) AF: 0.00442 AC: 193 AN: 43630

GnomAD4 genome AF: 0.00742 AC: 1124 AN: 151438 Hom.: 6 Cov.: 31 AF XY: 0.00713 AC XY: 528 AN XY: 74004

African (AFR) AF: 0.0193 AC: 799 AN: 41462

American (AMR) AF: 0.00605 AC: 92 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 65 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.0000977 AC: 1 AN: 10236

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 67784

Other (OTH) AF: 0.00809 AC: 17 AN: 2102

Alfa AF: 0.00728 Hom.: 0

Bravo AF: 0.00839

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	not specified (3)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism

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: rs78926093; hg19: chr19-15288695;