rs368181126

chr19-15187216-T-Cchr19-15187216-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

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 frequency of 0.0000266 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no 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:1 B:1
• Conservation: PhyloP100: 0.398

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000435.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.18203616).
• BP6: Variant 19-15187216-T-C is Benign according to our data. Variant chr19-15187216-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447797.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.1729A>G	p.Thr577Ala	missense_variant	11/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.1729A>G	p.Thr577Ala	missense_variant	11/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.1729A>G	p.Thr577Ala	missense_variant	11/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.1726A>G	p.Thr576Ala	missense_variant	11/23	5

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250702 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135774

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 727196

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 02, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.66	T;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.50	N;.
REVEL	Uncertain	0.48
Sift	Benign	0.53	T;.
Sift4G	Benign	0.67	T;T
Polyphen		0.0	B;.
Vest4		0.77
MVP		0.94
MPC		0.52
ClinPred		0.066	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs368181126; hg19: chr19-15298027;