rs55882518

chr19-15179039-T-Achr19-15179039-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000435.3(NOTCH3):c.3704A>T(p.His1235Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,614,210 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (34 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.213

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008857071).
• BP6: Variant 19-15179039-T-A is Benign according to our data. Variant chr19-15179039-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328393.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chr19-15179039-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00411 (626/152354) while in subpopulation NFE AF= 0.00622 (423/68032). AF 95% confidence interval is 0.00573. There are 3 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.3704A>T	p.His1235Leu	missense_variant	22/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.3548A>T	p.His1183Leu	missense_variant	21/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.3704A>T	p.His1235Leu	missense_variant	22/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.3545A>T	p.His1182Leu	missense_variant	21/23	5
NOTCH3	ENST00000595045.1	n.540A>T		non_coding_transcript_exon_variant	2/3	2
NOTCH3	ENST00000600841.1	n.182A>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 626 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00425 AC: 1065 AN: 250562 Hom.: 1 AF XY: 0.00430 AC XY: 583 AN XY: 135680

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00636

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00585 AC: 8551 AN: 1461856 Hom.: 34 Cov.: 36 AF XY: 0.00573 AC XY: 4164 AN XY: 727226

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.0185

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00677

Gnomad4 OTH exome AF: 0.00497

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74510

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00662 Hom.: 2

Bravo AF: 0.00437

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NOTCH3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 02, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.5
Dann	Benign	0.81
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.11	T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.4	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.18
Sift	Benign	0.030	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.0	B;.
Vest4		0.24
MVP		0.50
MPC		0.52
ClinPred		0.0077	T
GERP RS		-1.0
Varity_R		0.15
gMVP		0.49

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: rs55882518; hg19: chr19-15289850;