rs75617410

Variant names:

• chr19-15187325-C-A
• rs75617410
• NM_000435.3:c.1620G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-15187325-C-A
• chr19-15187325-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000263388.7(NOTCH3):​c.1620G>T​(p.Thr540Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,490 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T540T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (24 hom.)
• Consequence: NOTCH3 ENST00000263388.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.75
• Publications: 6 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: 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-15187325-C-A is Benign according to our data. Variant chr19-15187325-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00133 (203/152316) while in subpopulation EAS AF = 0.0342 (177/5174). AF 95% confidence interval is 0.0301. There are 3 homozygotes in GnomAd4. There are 119 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: ENST00000263388.7. 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.1620G>T	p.Thr540Thr	synonymous	Exon 11 of 33	NP_000426.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.1620G>T	p.Thr540Thr	synonymous	Exon 11 of 33	ENSP00000263388.1
	NOTCH3	ENST00000601011.1	TSL:5	c.1617G>T	p.Thr539Thr	synonymous	Exon 11 of 23	ENSP00000473138.1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152198 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00300 AC: 748 AN: 249694 AF XY: 0.00263

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.0377

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000973 AC: 1422 AN: 1461174 Hom.: 24 Cov.: 33 AF XY: 0.000927 AC XY: 674 AN XY: 726912

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000895 AC: 4 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26124

East Asian (EAS) AF: 0.0299 AC: 1187 AN: 39692

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86226

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52986

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111832

Other (OTH) AF: 0.00174 AC: 105 AN: 60372

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00160 AC XY: 119 AN XY: 74474

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5174

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00147 Hom.: 4

Bravo AF: 0.00172

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.029
DANN	Benign	0.57
PhyloP100		-6.7
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: rs75617410; hg19: chr19-15298136; COSMIC: COSV99656060;