rs559253584

Positions:

• chr9-136503068-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017617.5(NOTCH1):​c.5167+114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,469,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.426

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.5167+114C>T		intron_variant		ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.4444+114C>T		intron_variant			XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5167+114C>T		intron_variant			NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000395 AC: 87 AN: 220222 Hom.: 1 AF XY: 0.000321 AC XY: 39 AN XY: 121572

Gnomad AFR exome AF: 0.000225

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.0000792

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000217 AC: 286 AN: 1317728 Hom.: 0 Cov.: 20 AF XY: 0.000210 AC XY: 139 AN XY: 661872

Gnomad4 AFR exome AF: 0.000129

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.0000797

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74444

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.000404

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.57

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

LitVar

Other links and lift over

dbSNP: rs559253584; hg19: chr9-139397520;