NM_017617.5:c.5639-174G>A

Variant names:

• chr9-136501021-C-T
• rs3124999
• NM_017617.5:c.5639-174G>A

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.5639-174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,102 control chromosomes in the GnomAD database, including 15,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (15465 hom., cov: 33)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.716

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 9-136501021-C-T is Benign according to our data. Variant chr9-136501021-C-T is described in ClinVar as [Benign]. Clinvar id is 677905.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.5639-174G>A		intron_variant	Intron 30 of 33	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.4916-174G>A		intron_variant	Intron 27 of 30		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5639-174G>A		intron_variant	Intron 30 of 33		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66430 AN: 151982 Hom.: 15448 Cov.: 33

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.880

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.418

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.437 AC: 66484 AN: 152102 Hom.: 15465 Cov.: 33 AF XY: 0.443 AC XY: 32918 AN XY: 74358

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.483

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.880

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.422

Alfa AF: 0.389 Hom.: 5954

Bravo AF: 0.451

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.62

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: rs3124999; hg19: chr9-139395473; COSMIC: COSV53098650; COSMIC: COSV53098650;