9-136505524-C-T

Position:

• chr9-136505524-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_017617.5(NOTCH1):​c.4372G>A​(p.Ala1458Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000943 in 1,612,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.32

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 -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09777126).
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.4372G>A	p.Ala1458Thr	missense_variant	25/34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.3649G>A	p.Ala1217Thr	missense_variant	22/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.4372G>A	p.Ala1458Thr	missense_variant	25/34		NM_017617.5	ENSP00000498587	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000893 AC: 22 AN: 246410 Hom.: 0 AF XY: 0.0000892 AC XY: 12 AN XY: 134546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.0000925 AC: 135 AN: 1460118 Hom.: 0 Cov.: 33 AF XY: 0.0000977 AC XY: 71 AN XY: 726372

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000926

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74504

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000973 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000663 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adams-Oliver syndrome 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2016

The p.A1458T variant (also known as c.4372G>A), located in coding exon 25 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 4372. The alanine at codon 1458 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs200495793. Based on data from ExAC, the A allele has an overall frequency of <0.01% (7/103644). Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.83% (1/120) Colombian alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12676) total alleles studied and 0.01% (1/8440) European American alleles. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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 alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36307044) -

Aortic valve disease 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.18
Sift	Benign	0.032	D
Sift4G	Benign	0.21	T
Polyphen		0.0020	B
Vest4		0.32
MVP		0.76
MPC		0.37
ClinPred		0.050	T
GERP RS		1.9
Varity_R		0.13

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: rs200495793; hg19: chr9-139399976;