rs191645600

Variant names:

• chr9-136505728-G-T
• rs191645600
• NM_017617.5:c.4168C>A
• NOTCH1 p.Pro1390Thr

Your query was ambiguous. Multiple possible variants found:

• chr9-136505728-G-T
• chr9-136505728-G-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.4168C>A​(p.Pro1390Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,595,712 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. P1390L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12 O:1
• Conservation: PhyloP100: 6.14
• Publications: 17 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36219618).
• BP6: Variant 9-136505728-G-T is Benign according to our data. Variant chr9-136505728-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134935.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000571 (87/152362) while in subpopulation NFE AF = 0.00106 (72/68030). AF 95% confidence interval is 0.000861. There are 1 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 87 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.4168C>A	p.Pro1390Thr	missense	Exon 25 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.4168C>A	p.Pro1390Thr	missense	Exon 25 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.4057C>A	p.Pro1353Thr	missense	Exon 25 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.4054C>A	p.Pro1352Thr	missense	Exon 24 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.000571 AC: 87 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000580 AC: 134 AN: 231072 AF XY: 0.000584

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000997

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000545

GnomAD4 exome AF: 0.00120 AC: 1731 AN: 1443350 Hom.: 2 Cov.: 33 AF XY: 0.00120 AC XY: 862 AN XY: 715512

African (AFR) AF: 0.000151 AC: 5 AN: 33050

American (AMR) AF: 0.000115 AC: 5 AN: 43344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.00 AC: 0 AN: 84866

European-Finnish (FIN) AF: 0.0000584 AC: 3 AN: 51328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00152 AC: 1672 AN: 1101056

Other (OTH) AF: 0.000774 AC: 46 AN: 59396

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.000429 AC XY: 32 AN XY: 74512

African (AFR) AF: 0.000313 AC: 13 AN: 41588

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000821 Hom.: 1

Bravo AF: 0.000650

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	2	not specified (4)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Adams-Oliver syndrome 5 (1)
-	1	-	Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 (1)
-	-	1	Connective tissue disorder (1)
-	1	-	Heart, malformation of (1)
-	-	1	NOTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.097
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Benign	0.036	D
Sift4G	Benign	0.27	T
Varity_R		0.21
Mutation Taster		=78/22	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs191645600;

hg19: chr9-139400180;

COSMIC: COSV53103214;