chr19-15179039-T-A

Variant names:

• chr19-15179039-T-A
• rs55882518
• NM_000435.3:c.3704A>T

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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
• Publications: 14 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]

MIR6795 (HGNC:50031): (microRNA 6795) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 328393.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000435.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.3704A>T	p.His1235Leu	missense	Exon 22 of 33	NP_000426.2
	MIR6795	NR_106853.1		n.*244A>T		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.3704A>T	p.His1235Leu	missense	Exon 22 of 33	ENSP00000263388.1
	NOTCH3	ENST00000601011.1	TSL:5	c.3545A>T	p.His1182Leu	missense	Exon 21 of 23	ENSP00000473138.1
	NOTCH3	ENST00000595045.1	TSL:2	n.540A>T		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.00425 AC: 1065 AN: 250562 AF XY: 0.00430

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33480

American (AMR) AF: 0.00344 AC: 154 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 483 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53392

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5762

European-Non Finnish (NFE) AF: 0.00677 AC: 7532 AN: 1112010

Other (OTH) AF: 0.00497 AC: 300 AN: 60396

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

African (AFR) AF: 0.00132 AC: 55 AN: 41580

American (AMR) AF: 0.00503 AC: 77 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 423 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.11	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.21
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.18
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0040	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
Mutation Taster		=98/2	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: rs55882518; hg19: chr19-15289850;