9-136496065-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017617.5(NOTCH1):c.*6G>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 0.00307 in 1,596,314 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (45 hom.)
• Consequence: NOTCH1 NM_017617.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.485

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-136496065-C-T is Benign according to our data. Variant chr9-136496065-C-T is described in ClinVar as [Benign]. Clinvar id is 281156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2079/152284) while in subpopulation AFR AF= 0.0444 (1845/41556). AF 95% confidence interval is 0.0427. There are 38 homozygotes in gnomad4. There are 1007 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2073 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.*6G>A		3_prime_UTR_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.*6G>A		3_prime_UTR_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.*6G>A		3_prime_UTR_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2073 AN: 152168 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00389 AC: 862 AN: 221680 Hom.: 9 AF XY: 0.00325 AC XY: 395 AN XY: 121614

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00340

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000354

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000583

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00195 AC: 2816 AN: 1444030 Hom.: 45 Cov.: 31 AF XY: 0.00178 AC XY: 1276 AN XY: 717632

Gnomad4 AFR exome AF: 0.0449

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.000164

Gnomad4 NFE exome AF: 0.000452

Gnomad4 OTH exome AF: 0.00488

GnomAD4 genome AF: 0.0137 AC: 2079 AN: 152284 Hom.: 38 Cov.: 33 AF XY: 0.0135 AC XY: 1007 AN XY: 74470

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.00844

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00613 Hom.: 7

Bravo AF: 0.0157

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 15, 2016

- -

Aortic valve disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Adams-Oliver syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.8
Dann	Benign	0.86

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: rs73668310; hg19: chr9-139390517; COSMIC: COSV53090138;