rs140567100

chr19-15162483-C-Achr19-15162483-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000435.3(NOTCH3):c.5895G>T(p.Lys1965Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,260 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K1965K) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.5895G>T	p.Lys1965Asn	missense_variant	32/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.5739G>T	p.Lys1913Asn	missense_variant	31/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.5895G>T	p.Lys1965Asn	missense_variant	32/33	1	NM_000435.3	P1
NOTCH3	ENST00000597756.1	c.411G>T	p.Lys137Asn	missense_variant	3/3	2
NOTCH3	ENST00000595514.1	c.*103G>T		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74434

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.45		Loss of ubiquitination at K1965 (P = 0.0087);
MVP		0.63
MPC		1.4
ClinPred		0.98	D
GERP RS		-2.8
Varity_R		0.41
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15273294;