rs375408767

Variant names:

• chr9-136503326-T-A
• rs375408767
• NM_017617.5:c.5023A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136503326-T-A
• chr9-136503326-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017617.5(NOTCH1):​c.5023A>T​(p.Ile1675Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1675V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 0 publications found

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]

NOTCH1 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Adams-Oliver syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• aortic valve disease 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leukodystrophy

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.5023A>T	p.Ile1675Phe	missense_variant	Exon 27 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.4300A>T	p.Ile1434Phe	missense_variant	Exon 24 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5023A>T	p.Ile1675Phe	missense_variant	Exon 27 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460434 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726482

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.20
Sift	Uncertain	0.026	D
Sift4G	Benign	0.39	T
Polyphen		0.99	D
Vest4		0.76
MutPred		0.56		Gain of sheet (P = 0.0477);
MVP		0.52
MPC		2.3
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.60
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs375408767; hg19: chr9-139397778;