NOTCH3 p.Thr577Ala

Variant names:

• chr19-15187216-T-C
• rs368181126
• NM_000435.3:c.1729A>G
• NOTCH3 p.Thr577Ala

Your query was ambiguous. Multiple possible variants found:

• chr19-15187216-T-C
• chr19-15187214-TGT-AGC
• chr19-15187214-TGT-CGC
• chr19-15187214-TGT-GGC

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM1BP6

The NM_000435.3(NOTCH3):c.1729A>G (p.Thr577Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000266 (AC=43) in the gnomAD database across 1,613,988 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000453. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.398
• Publications: 4 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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 11 pathogenic, 5 benign rare missense variants (OR vs. background: 10.5).; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.1729A>G p.Thr577Ala	missense	Exon 11 of 33	Prot: NP_000426.2 UniProt:

NOTCH3 NM_000435.3

MANE Select

HGVSc / HGVSpc.1729A>Gp.Thr577Ala

Exon rankExon 11 of 33

missense

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.1729A>G p.Thr577Ala	missense	Exon 11 of 33	Prot: ENSP00000263388.1 UniProt:
	NOTCH3 ENST00000931534.1		c.1729A>G p.Thr577Ala	missense	Exon 11 of 34	Prot: ENSP00000601593.1 UniProt:
	NOTCH3 ENST00000931532.1		c.1708A>G p.Thr570Ala	missense	Exon 11 of 32	Prot: ENSP00000601591.1 UniProt:

NOTCH3 ENST00000263388.7

TSL:1MANE Select

HGVSc / HGVSpc.1729A>Gp.Thr577Ala

Exon rankExon 11 of 33

missense

Prot: ENSP00000263388.1UniProt: Q9UM47

NOTCH3 ENST00000931534.1

HGVSc / HGVSpc.1729A>Gp.Thr577Ala

Exon rankExon 11 of 34

missense

Prot: ENSP00000601593.1UniProt: A0ACI8TLY8

NOTCH3 ENST00000931532.1

HGVSc / HGVSpc.1708A>Gp.Thr570Ala

Exon rankExon 11 of 32

missense

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: 0.0000328	AC:5	Hom:0	AN:152222	Cov:33
GnomAD2 exomes	AF: 0.0000239	AC:6	Hom:	AN:250702	Cov:
GnomAD4 exome	AF: 0.0000260	AC:38	Hom:0	AN:1461766	Cov:33
GnomAD4 genome	AF: 0.0000328	AC:5	Hom:0	AN:152222	Cov:33
TOPMed (Bravo)	AF: 0.0000945	AC:25	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000405	AC:16	Hom:0	AN:39510	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
Qatari Genome	AF: 0.00370	AC:7	Hom:	AN:1882	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000953	4	41958	0.0000449	3	66888
SCHEMA(Schizophrenia)	0.000935	96	102680	0.000792	136	171756

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

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.64	D
FuncVEP CTI	Benign	0.0038
GPN-Star LLR	N/A	-4.2
GPN-Star score	N/A	4.2
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.64	T
Mutation Taster	N/A	31/69	disease causing
MutationAssessor	Benign	1.2	L
PhyloP100	Benign	0.40
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.48
Sift	Benign	0.53	T
Sift4G	Benign	0.67	T
Varity_R	N/A	0.15
VESM-3B	Benign	-2.3

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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: rs368181126;

hg19: chr19-15298027;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar