19-15187220-C-G

Variant names:

• chr19-15187220-C-G
• rs79926127
• NM_000435.3:c.1725G>C
• NOTCH3 p.Thr575Thr

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-9 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -9 classification points (ACMG Germline Pathogenicity v2019). BP4_StrongBP6_StrongBP7

The NM_000435.3(NOTCH3):c.1725G>C (p.Thr575Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000483 (AC=78) in the gnomAD database across 1,613,954 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000503. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.82
• Publications: 10 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics
• 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
• inherited thrombocytopenia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000435.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NOTCH3 NM_000435.3	MANE Select	c.1725G>C p.Thr575Thr	synonymous	Exon 11 of 33	Prot: NP_000426.2 UniProt:

NOTCH3 NM_000435.3

MANE Select

HGVSc / HGVSpc.1725G>Cp.Thr575Thr

Exon rankExon 11 of 33

synonymous

Prot: NP_000426.2UniProt: Q9UM47

Ensembl Transcripts

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

NOTCH3 ENST00000263388.7

TSL:1MANE Select

HGVSc / HGVSpc.1725G>Cp.Thr575Thr

Exon rankExon 11 of 33

synonymous

Prot: ENSP00000263388.1UniProt: Q9UM47

NOTCH3 ENST00000931534.1

HGVSc / HGVSpc.1725G>Cp.Thr575Thr

Exon rankExon 11 of 34

synonymous

Prot: ENSP00000601593.1UniProt: A0ACI8TLY8

NOTCH3 ENST00000931532.1

HGVSc / HGVSpc.1704G>Cp.Thr568Thr

Exon rankExon 11 of 32

synonymous

Prot: ENSP00000601591.1UniProt: A0ACI8TLB6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000591	AC:9	Hom:0	AN:152186	Cov:33
GnomAD2 exomes	AF: 0.0000279	AC:7	Hom:	AN:250726	Cov:
GnomAD4 exome	AF: 0.0000472	AC:69	Hom:0	AN:1461768	Cov:33
GnomAD4 genome	AF: 0.0000591	AC:9	Hom:0	AN:152186	Cov:33
TOPMed (Bravo)	AF: 0.0000567	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000120	AC:1	Hom:5	AN:83050	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000330	AC:4	Hom:0	AN:122310	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888
SCHEMA(Schizophrenia)	0.0000291	3	103256	0.0000173	3	173508

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0015
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.42
DANN	Benign	0.68
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.5
PhyloP100	Benign	-6.8

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs79926127;

hg19: chr19-15298031;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar