19-15179196-C-T

Variant names:

• chr19-15179196-C-T
• rs10408676
• NM_000435.3:c.3547G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.3547G>A​(p.Val1183Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,932 control chromosomes in the GnomAD database, including 2,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1183A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.076 (1277 hom., cov: 34)
  • Exomes 𝑓: 0.013 (1237 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.97
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024884641).
• BP6: Variant 19-15179196-C-T is Benign according to our data. Variant chr19-15179196-C-T is described in ClinVar as Benign. ClinVar VariationId is 256133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.3547G>A	p.Val1183Met	missense	Exon 22 of 33	NP_000426.2	Q9UM47
	MIR6795	NR_106853.1		n.*87G>A		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.3547G>A	p.Val1183Met	missense	Exon 22 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.3682G>A	p.Val1228Met	missense	Exon 23 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.3370G>A	p.Val1124Met	missense	Exon 21 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11553 AN: 152090 Hom.: 1271 Cov.: 34

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00646

Gnomad OTH AF: 0.0541

GnomAD2 exomes AF: 0.0253 AC: 6341 AN: 250230 AF XY: 0.0218

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00233

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0135 AC: 19696 AN: 1461722 Hom.: 1237 Cov.: 36 AF XY: 0.0130 AC XY: 9469 AN XY: 727144

African (AFR) AF: 0.251 AC: 8416 AN: 33476

American (AMR) AF: 0.0164 AC: 732 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 683 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0219 AC: 1891 AN: 86252

European-Finnish (FIN) AF: 0.00223 AC: 119 AN: 53308

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5768

European-Non Finnish (NFE) AF: 0.00565 AC: 6285 AN: 1111968

Other (OTH) AF: 0.0236 AC: 1424 AN: 60394

GnomAD4 genome AF: 0.0760 AC: 11570 AN: 152210 Hom.: 1277 Cov.: 34 AF XY: 0.0729 AC XY: 5425 AN XY: 74424

African (AFR) AF: 0.247 AC: 10252 AN: 41508

American (AMR) AF: 0.0290 AC: 444 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0184 AC: 89 AN: 4828

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00646 AC: 439 AN: 67996

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0313 Hom.: 1601

Bravo AF: 0.0859

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.242 AC: 1066

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.0297 AC: 3608

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00557

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.64
Sift	Benign	0.035	D
Sift4G	Uncertain	0.017	D
Polyphen		0.70	P
Vest4		0.14
MPC		0.73
ClinPred		0.013	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.49
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10408676; hg19: chr19-15290007; COSMIC: COSV54643886;