NM_017617.5:c.1787C>T

Variant names:

• chr9-136515599-G-A
• rs61755997
• NM_017617.5:c.1787C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.1787C>T​(p.Thr596Met) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,609,616 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T596T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 5.63
• Publications: 14 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: Orphanet, Illumina
• Adams-Oliver syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• NOTCH1-related AOS spectrum disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• aortic valve disease 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• 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

LOC124902310 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• BP6: Variant 9-136515599-G-A is Benign according to our data. Variant chr9-136515599-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264528.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000197 (30/152310) while in subpopulation EAS AF = 0.000771 (4/5186). AF 95% confidence interval is 0.000279. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 30 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	NM_017617.5	MANE Select	c.1787C>T	p.Thr596Met	missense	Exon 11 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.1787C>T	p.Thr596Met	missense	Exon 11 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.1676C>T	p.Thr559Met	missense	Exon 11 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.1673C>T	p.Thr558Met	missense	Exon 10 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000149 AC: 36 AN: 240946 AF XY: 0.0000986

Gnomad AFR exome AF: 0.000601

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0000542

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1457306 Hom.: 2 Cov.: 34 AF XY: 0.000153 AC XY: 111 AN XY: 725042

African (AFR) AF: 0.000568 AC: 19 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86118

European-Finnish (FIN) AF: 0.000100 AC: 5 AN: 50010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111488

Other (OTH) AF: 0.000199 AC: 12 AN: 60254

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74496

African (AFR) AF: 0.000433 AC: 18 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000459 AC: 2

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000183 AC: 22

EpiCase AF: 0.000109

EpiControl AF: 0.000179

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.65
Sift	Benign	0.45	T
Sift4G	Benign	0.17	T
Polyphen		0.94	P
Vest4		0.80
MVP		0.85
MPC		0.87
ClinPred		0.13	T
GERP RS		5.2
Varity_R		0.10
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs61755997; hg19: chr9-139410051; COSMIC: COSV53031613; COSMIC: COSV53031613;