rs112197217

Variant names:

• chr19-15179425-G-T
• rs112197217
• NM_000435.3:c.3399C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-15179425-G-T
• chr19-15179425-G-A
• chr19-15179425-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000435.3(NOTCH3):​c.3399C>A​(p.His1133Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,984 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 33)
  • Exomes 𝑓: 0.017 (245 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.668
• Publications: 25 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000435.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.01282531).
• BP6: Variant 19-15179425-G-T is Benign according to our data. Variant chr19-15179425-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1793/152156) while in subpopulation NFE AF = 0.0204 (1385/67996). AF 95% confidence interval is 0.0195. There are 18 homozygotes in GnomAd4. There are 811 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	NM_000435.3	MANE Select	c.3399C>A	p.His1133Gln	missense	Exon 21 of 33	NP_000426.2	Q9UM47
	MIR6795	NR_106853.1		n.-75C>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.3399C>A	p.His1133Gln	missense	Exon 21 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.3534C>A	p.His1178Gln	missense	Exon 22 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.3222C>A	p.His1074Gln	missense	Exon 20 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1793 AN: 152038 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.0100 AC: 2514 AN: 251328 AF XY: 0.00980

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0166 AC: 24195 AN: 1461828 Hom.: 245 Cov.: 36 AF XY: 0.0159 AC XY: 11549 AN XY: 727228

African (AFR) AF: 0.00215 AC: 72 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000904 AC: 78 AN: 86258

European-Finnish (FIN) AF: 0.0158 AC: 843 AN: 53366

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0199 AC: 22118 AN: 1112000

Other (OTH) AF: 0.0135 AC: 813 AN: 60396

GnomAD4 genome AF: 0.0118 AC: 1793 AN: 152156 Hom.: 18 Cov.: 33 AF XY: 0.0109 AC XY: 811 AN XY: 74390

African (AFR) AF: 0.00325 AC: 135 AN: 41516

American (AMR) AF: 0.00608 AC: 93 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5144

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0204 AC: 1385 AN: 67996

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.0158 Hom.: 84

Bravo AF: 0.0102

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0181 AC: 156

ExAC AF: 0.0102 AC: 1238

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0141

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (1)
-	-	1	Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	3.9
DANN	Benign	0.95
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.67
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.29	B
Vest4		0.45
MutPred		0.74		Gain of disorder (P = 0.0349)
MPC		0.97
ClinPred		0.077	T
GERP RS		-8.6
Varity_R		0.18
gMVP		0.37
Mutation Taster		=87/13	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: rs112197217; hg19: chr19-15290236;