chr9-136517274-G-A

Variant names:

• chr9-136517274-G-A
• rs377535397
• NM_017617.5:c.1553C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.1553C>T​(p.Thr518Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000916 in 1,593,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T518R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense, splice_region
• Scores: Splicing: ADA: 0.1050
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 5.15
• Publications: 6 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

LOC124902310 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045786798).
• BP6: Variant 9-136517274-G-A is Benign according to our data. Variant chr9-136517274-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373661.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000427 (65/152230) while in subpopulation AFR AF = 0.00152 (63/41548). AF 95% confidence interval is 0.00122. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 65 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017617.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	NM_017617.5	MANE Select	c.1553C>T	p.Thr518Met	missense splice_region	Exon 9 of 34	NP_060087.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.1553C>T	p.Thr518Met	missense splice_region	Exon 9 of 34	ENSP00000498587.1
	NOTCH1	ENST00000680668.1		c.1553C>T	p.Thr518Met	missense splice_region	Exon 9 of 33	ENSP00000506336.1
	NOTCH1	ENST00000680218.1		c.1553C>T	p.Thr518Met	missense splice_region	Exon 9 of 34	ENSP00000505339.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152112 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 24 AN: 223710 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000562 AC: 81 AN: 1441442 Hom.: 0 Cov.: 32 AF XY: 0.0000419 AC XY: 30 AN XY: 716046

African (AFR) AF: 0.00163 AC: 54 AN: 33050

American (AMR) AF: 0.0000230 AC: 1 AN: 43536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 38908

South Asian (SAS) AF: 0.00 AC: 0 AN: 83882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000209 AC: 23 AN: 1100304

Other (OTH) AF: 0.0000504 AC: 3 AN: 59534

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152230 Hom.: 1 Cov.: 34 AF XY: 0.000376 AC XY: 28 AN XY: 74418

African (AFR) AF: 0.00152 AC: 63 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.000744 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000142 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Adams-Oliver syndrome 5 (1)
-	1	-	Aortic valve disease 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)
-	-	1	NOTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.046	T
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Benign	0.99	L
PhyloP100		5.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.41
Sift	Benign	0.034	D
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.39
MVP		0.82
MPC		0.58
ClinPred		0.11	T
GERP RS		3.0
Varity_R		0.17
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.41
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: rs377535397; hg19: chr9-139411726; COSMIC: COSV53052357;