19-15161407-G-T

Variant names:

• chr19-15161407-G-T
• rs114447350
• NM_000435.3:c.6221C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_000435.3(NOTCH3):​c.6221C>A​(p.Pro2074Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000728 in 1,373,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2074L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.61
• Publications: 9 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myofibromatosis, infantile, 2

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27420065).
• BP6: Variant 19-15161407-G-T is Benign according to our data. Variant chr19-15161407-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3715750.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.6221C>A	p.Pro2074Gln	missense_variant	Exon 33 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.6065C>A	p.Pro2022Gln	missense_variant	Exon 32 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.6221C>A	p.Pro2074Gln	missense_variant	Exon 33 of 33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000595514.1	n.*429C>A		downstream_gene_variant		3		ENSP00000470661.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 1 AN: 124650 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373112 Hom.: 0 Cov.: 36 AF XY: 0.00000148 AC XY: 1 AN XY: 675266

African (AFR) AF: 0.00 AC: 0 AN: 30672

American (AMR) AF: 0.00 AC: 0 AN: 32008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23960

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35520

South Asian (SAS) AF: 0.00 AC: 0 AN: 77266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4924

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068474

Other (OTH) AF: 0.00 AC: 0 AN: 56620

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Benign	0.34	T
Sift4G	Benign	0.41	T
Polyphen		0.64	P
Vest4		0.34
MutPred		0.14		Gain of solvent accessibility (P = 0.0202);
MVP		0.96
MPC		0.60
ClinPred		0.23	T
GERP RS		3.8
Varity_R		0.090
gMVP		0.52
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs114447350; hg19: chr19-15272218;