9-136495945-C-T

Variant names:

• chr9-136495945-C-T
• rs3124591
• NM_017617.5:c.*126G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.*126G>A		3_prime_UTR_variant	Exon 34 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.*126G>A		3_prime_UTR_variant	Exon 31 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.*126G>A		3_prime_UTR_variant	Exon 34 of 34		NM_017617.5	ENSP00000498587.1

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

African (AFR) AF: 0.842 AC: 17027 AN: 20224

American (AMR) AF: 0.660 AC: 12721 AN: 19260

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 9778 AN: 17794

East Asian (EAS) AF: 0.902 AC: 29495 AN: 32688

South Asian (SAS) AF: 0.663 AC: 35713 AN: 53854

European-Finnish (FIN) AF: 0.519 AC: 14986 AN: 28848

Middle Eastern (MID) AF: 0.557 AC: 1616 AN: 2900

European-Non Finnish (NFE) AF: 0.488 AC: 320167 AN: 656408

Other (OTH) AF: 0.558 AC: 22148 AN: 39662

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

African (AFR) AF: 0.832 AC: 34534 AN: 41528

American (AMR) AF: 0.632 AC: 9663 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1963 AN: 3470

East Asian (EAS) AF: 0.938 AC: 4870 AN: 5190

South Asian (SAS) AF: 0.665 AC: 3208 AN: 4824

European-Finnish (FIN) AF: 0.516 AC: 5452 AN: 10556

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33430 AN: 67978

Other (OTH) AF: 0.593 AC: 1254 AN: 2114

Alfa AF: 0.568 Hom.: 6392

Bravo AF: 0.643

Asia WGS AF: 0.785 AC: 2729 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.66
PhyloP100		0.20
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

Publications

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Other links and lift over

dbSNP: rs3124591; hg19: chr9-139390397;