rs61751536

chr9-136502481-G-Achr9-136502481-G-Cchr9-136502481-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017617.5(NOTCH1):c.5175C>T(p.Thr1725=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,562,170 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.15

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-136502481-G-A is Benign according to our data. Variant chr9-136502481-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502481-G-A is described in Lovd as [Benign]. Variant chr9-136502481-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.15 with no splicing effect.
• BS2: High AC in GnomAd at 349 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.5175C>T	p.Thr1725=	synonymous_variant	28/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.4452C>T	p.Thr1484=	synonymous_variant	25/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5175C>T	p.Thr1725=	synonymous_variant	28/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152098 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00244 AC: 413 AN: 169454 Hom.: 0 AF XY: 0.00243 AC XY: 230 AN XY: 94552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000211

Gnomad ASJ exome AF: 0.00952

Gnomad EAS exome AF: 0.0000732

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00239 AC: 3373 AN: 1409956 Hom.: 11 Cov.: 32 AF XY: 0.00243 AC XY: 1691 AN XY: 697198

Gnomad4 AFR exome AF: 0.000248

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00276

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00229 AC: 348 AN: 152214 Hom.: 1 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74418

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00377 Hom.: 0

Bravo AF: 0.00190

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NOTCH1: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2017	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 14, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Adams-Oliver syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Aortic valve disease 1 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	-0.72
Cadd	Benign	5.8
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61751536; hg19: chr9-139396933;