rs200207651

Variant names:

• chr9-136508926-C-T
• rs200207651
• NM_017617.5:c.3115G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-136508926-C-T
• chr9-136508926-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017617.5(NOTCH1):​c.3115G>A​(p.Gly1039Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000476 in 1,549,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.20
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010801673).
• BP6: Variant 9-136508926-C-T is Benign according to our data. Variant chr9-136508926-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 264180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000597 (91/152364) while in subpopulation NFE AF = 0.000456 (31/68034). AF 95% confidence interval is 0.000329. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 91 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.3115G>A	p.Gly1039Ser	missense	Exon 19 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.3115G>A	p.Gly1039Ser	missense	Exon 19 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.3004G>A	p.Gly1002Ser	missense	Exon 19 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.3001G>A	p.Gly1001Ser	missense	Exon 18 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000829 AC: 128 AN: 154310 AF XY: 0.000693

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000471

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.000603

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000462 AC: 646 AN: 1397090 Hom.: 0 Cov.: 35 AF XY: 0.000451 AC XY: 311 AN XY: 689172

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.000224 AC: 8 AN: 35794

Ashkenazi Jewish (ASJ) AF: 0.000516 AC: 13 AN: 25172

East Asian (EAS) AF: 0.0000558 AC: 2 AN: 35820

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79188

European-Finnish (FIN) AF: 0.00491 AC: 236 AN: 48044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4378

European-Non Finnish (NFE) AF: 0.000336 AC: 363 AN: 1079228

Other (OTH) AF: 0.000397 AC: 23 AN: 57872

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.000765 AC XY: 57 AN XY: 74512

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00489 AC: 52 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68034

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

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000244 AC: 1

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000251 AC: 26

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	2	not specified (2)
-	-	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	0.050
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.60
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.011	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.37
Sift	Benign	0.65	T
Sift4G	Benign	0.94	T
Polyphen		0.0040	B
Vest4		0.23
MVP		0.70
MPC		0.38
ClinPred		0.0088	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
Mutation Taster		=95/5	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: rs200207651; hg19: chr9-139403378;