9-136495945-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017617.5(NOTCH1):c.*126G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 1,023,792 control chromosomes in the GnomAD database, including 159,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (31436 hom., cov: 33)
  • Exomes 𝑓: 0.53 (128542 hom.)
• Consequence: NOTCH1 NM_017617.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.205

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136495945-C-T is Benign according to our data. Variant chr9-136495945-C-T is described in ClinVar as [Benign]. Clinvar id is 1256850.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-136495945-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.*126G>A		3_prime_UTR_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.*126G>A		3_prime_UTR_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.*126G>A		3_prime_UTR_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94695 AN: 152036 Hom.: 31388 Cov.: 33

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.532 AC: 463651 AN: 871638 Hom.: 128542 Cov.: 11 AF XY: 0.537 AC XY: 233676 AN XY: 435510

Gnomad4 AFR exome AF: 0.842

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.902

Gnomad4 SAS exome AF: 0.663

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.488

Gnomad4 OTH exome AF: 0.558

GnomAD4 genome AF: 0.623 AC: 94807 AN: 152154 Hom.: 31436 Cov.: 33 AF XY: 0.630 AC XY: 46880 AN XY: 74362

Gnomad4 AFR AF: 0.832

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.566

Gnomad4 EAS AF: 0.938

Gnomad4 SAS AF: 0.665

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.593

Alfa AF: 0.553 Hom.: 5353

Bravo AF: 0.643

Asia WGS AF: 0.785 AC: 2729 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.1
Dann	Benign	0.66

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: rs3124591; hg19: chr9-139390397;