rs368146879

Positions:

• chr19-15180229-G-A
• chr19-15180229-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_000435.3(NOTCH3):​c.3170C>T​(p.Ala1057Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 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 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.86

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 -3 ACMG points.

• PM1: In a domain EGF-like 27 (size 46) in uniprot entity NOTC3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000435.3
• BP6: Variant 19-15180229-G-A is Benign according to our data. Variant chr19-15180229-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447829.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr19-15180229-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.3170C>T	p.Ala1057Val	missense_variant	20/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.3014C>T	p.Ala1005Val	missense_variant	19/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.3170C>T	p.Ala1057Val	missense_variant	20/33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.3011C>T	p.Ala1004Val	missense_variant	19/23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 249958 Hom.: 1 AF XY: 0.000177 AC XY: 24 AN XY: 135464

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461424 Hom.: 1 Cov.: 34 AF XY: 0.000131 AC XY: 95 AN XY: 727018

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74384

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000172 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.93	L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.10	B;.
Vest4		0.20
MVP		0.88
MPC		0.44
ClinPred		0.029	T
GERP RS		1.4
Varity_R		0.036
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368146879; hg19: chr19-15291040; COSMIC: COSV54636397; COSMIC: COSV54636397;