rs201215245

chr9-136505865-G-Achr9-136505865-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_017617.5(NOTCH1):c.4031C>T(p.Thr1344Met) variant causes a missense change. The variant allele was found at a frequency of 0.000448 in 1,592,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1344R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 5.17

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP6: Variant 9-136505865-G-A is Benign according to our data. Variant chr9-136505865-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449810.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.4031C>T	p.Thr1344Met	missense_variant	25/34	ENST00000651671.1
NOTCH1	XM_011518717.3	c.3308C>T	p.Thr1103Met	missense_variant	22/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.4031C>T	p.Thr1344Met	missense_variant	25/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000445 AC: 96 AN: 215554 Hom.: 0 AF XY: 0.000500 AC XY: 60 AN XY: 120052

Gnomad AFR exome AF: 0.0000770

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000201

Gnomad NFE exome AF: 0.000887

Gnomad OTH exome AF: 0.000733

GnomAD4 exome AF: 0.000453 AC: 653 AN: 1440588 Hom.: 0 Cov.: 33 AF XY: 0.000468 AC XY: 335 AN XY: 716534

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000682

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000320

Gnomad4 NFE exome AF: 0.000549

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74338

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000556 AC: 2

ESP6500EA AF: 0.000533 AC: 4

ExAC AF: 0.000529 AC: 62

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2021	This variant is associated with the following publications: (PMID: 26820064) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2021	The p.T1344M variant (also known as c.4031C>T), located in coding exon 25 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 4031. The threonine at codon 1344 is replaced by methionine, an amino acid with similar properties. This alteration was described in patients with left-sided congenital heart disease (Kerstjens-Frederikse WS et al. Genet. Med., 2016 09;18:914-23). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 24, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 16, 2024

Variant summary: NOTCH1 c.4031C>T (p.Thr1344Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 215554 control chromosomes. The observed variant frequency is approximately 14-fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is benign. c.4031C>T has been reported in the literature as a VUS in individuals affected with left-sided congenital heart disease (Kerstjens-Frederikse_2016) and thoracic aortic aneurysm (Salmasi_2022), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26820064, 35830949). ClinVar contains an entry for this variant (Variation ID: 449810). Based on the evidence outlined above, the variant was classified as likely benign. -

Adams-Oliver syndrome 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Benign	0.068	T
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.67
MVP		0.40
MPC		1.1
ClinPred		0.39	T
GERP RS		4.7
Varity_R		0.14

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: rs201215245; hg19: chr9-139400317; COSMIC: COSV53044777; COSMIC: COSV53044777;