NM_000435.3:c.1725G>A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-6 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -6 classification points (ACMG Germline Pathogenicity v2019). PP3_ModerateBS2BP6_Strong

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 cumulative frequency of 0.00877 (AC=14,161) in the gnomAD database across 1,614,070 control chromosomes, including 74 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0109. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (71 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• 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: Likely_benign. The variant received -6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (12/12 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 74.; Very high cumulative gnomAD AC = 14161 (any gene).

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>A p.Thr575Thr	synonymous	Exon 11 of 33	Prot: NP_000426.2 UniProt:

NOTCH3 NM_000435.3

MANE Select

HGVSc / HGVSpc.1725G>Ap.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>A p.Thr575Thr	synonymous	Exon 11 of 33	Prot: ENSP00000263388.1 UniProt:
	NOTCH3 ENST00000931534.1		c.1725G>A p.Thr575Thr	synonymous	Exon 11 of 34	Prot: ENSP00000601593.1 UniProt:
	NOTCH3 ENST00000931532.1		c.1704G>A p.Thr568Thr	synonymous	Exon 11 of 32	Prot: ENSP00000601591.1 UniProt:

NOTCH3 ENST00000263388.7

TSL:1MANE Select

HGVSc / HGVSpc.1725G>Ap.Thr575Thr

Exon rankExon 11 of 33

synonymous

Prot: ENSP00000263388.1UniProt: Q9UM47

NOTCH3 ENST00000931534.1

HGVSc / HGVSpc.1725G>Ap.Thr575Thr

Exon rankExon 11 of 34

synonymous

Prot: ENSP00000601593.1UniProt: A0ACI8TLY8

NOTCH3 ENST00000931532.1

HGVSc / HGVSpc.1704G>Ap.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: 0.00711	AC:1082	Hom:3	AN:152186	Cov:33
GnomAD2 exomes	AF: 0.00786	AC:1970	Hom:	AN:250726	Cov:
GnomAD4 exome	AF: 0.00895	AC:13079	Hom:71	AN:1461766	Cov:33
GnomAD4 genome	AF: 0.00710	AC:1082	Hom:3	AN:152304	Cov:33
TOPMed (Bravo)	AF: 0.00809	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00633	AC:526	Hom:5	AN:83050	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00982	AC:23	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.00333	AC:1	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00838	AC:109	Hom:	AN:13006	Cov:
Qatari Genome	AF: 0.00930	AC:17	Hom:	AN:1828	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122310	Cov:
Turkish Variome	AF: 0.0194	AC:129	Hom:4	AN:6650	Cov:
UK10K	AF: 0.00846	AC:64	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000335	AC:3	Hom:0	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00522 *	58	11112	0.00465 *	82	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00844	240	28420	0.00832	240	28844
Epi25(Epilepsy)	0.00825	346	41958	0.0101	677	66888
SCHEMA(Schizophrenia)	0.00615	635	103252	0.00931	1615	173506

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.040
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.74
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
Mutation Taster	N/A	83/17	polymorphism
PhyloP100	Benign	-6.8

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Pathogenic	0.87	Position offset: -2
Pangolin (max)	Uncertain	0.30
Pangolin gain	Uncertain	0.30	Position offset: -2
SpliceAI score (max)	Pathogenic	0.87	Details are displayed if max score is > 0.2

Showing 4 of 4 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;

COSMIC: COSV54629762;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar