19-15160324-T-G

Variant names:

• chr19-15160324-T-G
• rs7247906
• NM_000435.3:c.*338A>C

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.*338A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 250,584 control chromosomes in the GnomAD database, including 101,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61836 hom., cov: 30)
  • Exomes 𝑓: 0.89 (39564 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13
• Publications: 7 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-15160324-T-G is Benign according to our data. Variant chr19-15160324-T-G is described in ClinVar as Benign. ClinVar VariationId is 328368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.969 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.*338A>C		3_prime_UTR	Exon 33 of 33	NP_000426.2	Q9UM47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.*338A>C		3_prime_UTR	Exon 33 of 33	ENSP00000263388.1	Q9UM47
	NOTCH3	ENST00000931534.1		c.*338A>C		3_prime_UTR	Exon 34 of 34	ENSP00000601593.1
	NOTCH3	ENST00000931532.1		c.*338A>C		3_prime_UTR	Exon 32 of 32	ENSP00000601591.1

Frequencies

GnomAD3 genomes AF: 0.903 AC: 136272 AN: 150960 Hom.: 61794 Cov.: 30

Gnomad AFR AF: 0.977

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.885

Gnomad NFE AF: 0.900

Gnomad OTH AF: 0.878

GnomAD4 exome AF: 0.890 AC: 88619 AN: 99534 Hom.: 39564 Cov.: 0 AF XY: 0.892 AC XY: 41838 AN XY: 46920

African (AFR) AF: 0.982 AC: 4354 AN: 4434

American (AMR) AF: 0.785 AC: 2554 AN: 3254

Ashkenazi Jewish (ASJ) AF: 0.877 AC: 4919 AN: 5608

East Asian (EAS) AF: 0.846 AC: 10071 AN: 11910

South Asian (SAS) AF: 0.898 AC: 1168 AN: 1300

European-Finnish (FIN) AF: 0.908 AC: 1053 AN: 1160

Middle Eastern (MID) AF: 0.874 AC: 493 AN: 564

European-Non Finnish (NFE) AF: 0.900 AC: 57081 AN: 63456

Other (OTH) AF: 0.883 AC: 6926 AN: 7848

GnomAD4 genome AF: 0.903 AC: 136359 AN: 151050 Hom.: 61836 Cov.: 30 AF XY: 0.899 AC XY: 66318 AN XY: 73806

African (AFR) AF: 0.977 AC: 40414 AN: 41352

American (AMR) AF: 0.784 AC: 11895 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.877 AC: 3044 AN: 3470

East Asian (EAS) AF: 0.807 AC: 4161 AN: 5156

South Asian (SAS) AF: 0.853 AC: 4099 AN: 4808

European-Finnish (FIN) AF: 0.885 AC: 8836 AN: 9986

Middle Eastern (MID) AF: 0.877 AC: 256 AN: 292

European-Non Finnish (NFE) AF: 0.900 AC: 61000 AN: 67806

Other (OTH) AF: 0.879 AC: 1850 AN: 2104

Alfa AF: 0.881 Hom.: 2846

Bravo AF: 0.896

Asia WGS AF: 0.849 AC: 2953 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.80
DANN	Benign	0.42
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7247906; hg19: chr19-15271135;