rs1044008

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000435.3(NOTCH3):c.6438G>A(p.Ala2146Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,539,680 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 111 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1220 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.73

Publications

12 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
lateral meningocele syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-15161190-C-T is Benign according to our data. Variant chr19-15161190-C-T is described in ClinVar as Benign. ClinVar VariationId is 256151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.73 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0311 (4732/152282) while in subpopulation NFE AF = 0.043 (2926/67996). AF 95% confidence interval is 0.0417. There are 111 homozygotes in GnomAd4. There are 2366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 111 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.6438G>A	p.Ala2146Ala	synonymous	Exon 33 of 33	NP_000426.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.6438G>A	p.Ala2146Ala	synonymous	Exon 33 of 33	ENSP00000263388.1
NOTCH3	ENST00000931534.1		c.6573G>A	p.Ala2191Ala	synonymous	Exon 34 of 34	ENSP00000601593.1
NOTCH3	ENST00000931532.1		c.6261G>A	p.Ala2087Ala	synonymous	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4733

AN:

152164

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00777

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0369

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0134

Gnomad FIN

AF:

0.0543

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0430

Gnomad OTH

AF:

0.0373

GnomAD2 exomes

AF:

0.0319

AC:

4332

AN:

135802

AF XY:

0.0308

show subpopulations

Gnomad AFR exome

AF:

0.00608

Gnomad AMR exome

AF:

0.0411

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.00178

Gnomad FIN exome

AF:

0.0549

Gnomad NFE exome

AF:

0.0427

Gnomad OTH exome

AF:

0.0351

GnomAD4 exome

AF:

0.0397

AC:

55073

AN:

1387398

Hom.:

1220

Cov.:

AF XY:

0.0391

AC XY:

26792

AN XY:

684784

show subpopulations

African (AFR)

AF:

0.00641

AC:

205

AN:

31998

American (AMR)

AF:

0.0408

AC:

1456

AN:

35664

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

875

AN:

25124

East Asian (EAS)

AF:

0.000686

AC:

AN:

36440

South Asian (SAS)

AF:

0.0141

AC:

1123

AN:

79390

European-Finnish (FIN)

AF:

0.0570

AC:

1971

AN:

34582

Middle Eastern (MID)

AF:

0.0532

AC:

294

AN:

5524

European-Non Finnish (NFE)

AF:

0.0435

AC:

47032

AN:

1080654

Other (OTH)

AF:

0.0361

AC:

2092

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3010

6021

9031

12042

15052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1738

3476

5214

6952

8690

<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:

0.0311

AC:

4732

AN:

152282

Hom.:

111

Cov.:

AF XY:

0.0318

AC XY:

2366

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00775

AC:

322

AN:

41570

American (AMR)

AF:

0.0368

AC:

563

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3472

East Asian (EAS)

AF:

0.000774

AC:

AN:

5166

South Asian (SAS)

AF:

0.0135

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0543

AC:

577

AN:

10626

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0430

AC:

2926

AN:

67996

Other (OTH)

AF:

0.0369

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

242

484

725

967

1209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0388

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

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

-0.84

CADD

Benign

0.14

(source)

DANN

Benign

0.25

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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