19-15187220-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_000435.3(NOTCH3):c.1725G>A(p.Thr575Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,614,070 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T575T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0089 ( 71 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -6.82

Publications

10 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
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

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-15187220-C-T is Benign according to our data. Variant chr19-15187220-C-T is described in ClinVar as Benign. ClinVar VariationId is 256122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0071 (1082/152304) while in subpopulation AMR AF = 0.0104 (159/15302). AF 95% confidence interval is 0.00949. There are 3 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.1725G>A	p.Thr575Thr	synonymous	Exon 11 of 33	NP_000426.2	Q9UM47

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.1725G>A	p.Thr575Thr	synonymous	Exon 11 of 33	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000931534.1		c.1725G>A	p.Thr575Thr	synonymous	Exon 11 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.1704G>A	p.Thr568Thr	synonymous	Exon 11 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00786

AC:

1970

AN:

250726

AF XY:

0.00803

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000972

Gnomad NFE exome

AF:

0.00969

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00895

AC:

13079

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00899

AC XY:

6540

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33480

American (AMR)

AF:

0.00825

AC:

369

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0283

AC:

740

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00677

AC:

584

AN:

86256

European-Finnish (FIN)

AF:

0.000919

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00948

AC:

10544

AN:

1112000

Other (OTH)

AF:

0.0111

AC:

671

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

799

1598

2396

3195

3994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00710

AC:

1082

AN:

152304

Hom.:

Cov.:

AF XY:

0.00673

AC XY:

501

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

41564

American (AMR)

AF:

0.0104

AC:

159

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00642

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

688

AN:

68024

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00756

Hom.:

Bravo

AF:

0.00809

EpiCase

AF:

0.0119

EpiControl

AF:

0.0131

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

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

-0.52

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

-6.8

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.87

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over