rs373713957

chr9-136523160-G-A

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.432C>T(p.Cys144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,604,098 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.198

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]

LOC124902310 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-136523160-G-A is Benign according to our data. Variant chr9-136523160-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136523160-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.198 with no splicing effect.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.432C>T	p.Cys144=	synonymous_variant	4/34	ENST00000651671.1
LOC124902310	XR_007061865.1	n.508-158G>A		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.20-3595C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.432C>T	p.Cys144=	synonymous_variant	4/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000484 AC: 110 AN: 227308 Hom.: 0 AF XY: 0.000531 AC XY: 66 AN XY: 124240

Gnomad AFR exome AF: 0.0000747

Gnomad AMR exome AF: 0.000909

Gnomad ASJ exome AF: 0.00301

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.0000703

Gnomad FIN exome AF: 0.0000533

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000534

GnomAD4 exome AF: 0.000377 AC: 548 AN: 1451870 Hom.: 3 Cov.: 31 AF XY: 0.000403 AC XY: 291 AN XY: 721444

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00304

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0000828

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.000325

Gnomad4 OTH exome AF: 0.000601

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152228 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74368

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NOTCH1: BP4, BP7 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 21, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 23, 2018	- -

Adams-Oliver syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

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	-0.47
Cadd	Benign	7.7
Dann	Benign	0.74

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: rs373713957; hg19: chr9-139417612; COSMIC: COSV53080257; COSMIC: COSV53080257;