9-136510809-C-T

Variant names:

• chr9-136510809-C-T
• rs3125001
• NM_017617.5:c.2588-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017617.5(NOTCH1):​c.2588-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,607,682 control chromosomes in the GnomAD database, including 145,459 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19496 hom., cov: 34)
  • Exomes 𝑓: 0.40 (125963 hom.)
• Consequence: NOTCH1 NM_017617.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002070
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.276
• Publications: 21 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: 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, 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

LOC124902310 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-136510809-C-T is Benign according to our data. Variant chr9-136510809-C-T is described in ClinVar as Benign. ClinVar VariationId is 281108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

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.2588-4G>A		splice_region intron	N/A	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.2588-4G>A		splice_region intron	N/A	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.2477-4G>A		splice_region intron	N/A	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.2474-4G>A		splice_region intron	N/A	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74146 AN: 151984 Hom.: 19467 Cov.: 34

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.475 AC: 113692 AN: 239218 AF XY: 0.459

Gnomad AFR exome AF: 0.658

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.875

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.383

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.404 AC: 587941 AN: 1455580 Hom.: 125963 Cov.: 62 AF XY: 0.402 AC XY: 291086 AN XY: 724460

African (AFR) AF: 0.655 AC: 21931 AN: 33470

American (AMR) AF: 0.578 AC: 25831 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 10992 AN: 26114

East Asian (EAS) AF: 0.824 AC: 32689 AN: 39684

South Asian (SAS) AF: 0.382 AC: 32914 AN: 86242

European-Finnish (FIN) AF: 0.461 AC: 21974 AN: 47636

Middle Eastern (MID) AF: 0.444 AC: 2544 AN: 5736

European-Non Finnish (NFE) AF: 0.371 AC: 412567 AN: 1111716

Other (OTH) AF: 0.439 AC: 26499 AN: 60298

GnomAD4 genome AF: 0.488 AC: 74242 AN: 152102 Hom.: 19496 Cov.: 34 AF XY: 0.493 AC XY: 36645 AN XY: 74350

African (AFR) AF: 0.646 AC: 26823 AN: 41522

American (AMR) AF: 0.509 AC: 7791 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1427 AN: 3466

East Asian (EAS) AF: 0.855 AC: 4395 AN: 5138

South Asian (SAS) AF: 0.374 AC: 1802 AN: 4816

European-Finnish (FIN) AF: 0.465 AC: 4922 AN: 10588

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25688 AN: 67952

Other (OTH) AF: 0.481 AC: 1016 AN: 2112

Alfa AF: 0.426 Hom.: 5804

Bravo AF: 0.505

Asia WGS AF: 0.620 AC: 2154 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	2	Aortic valve disease 1 (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.1
DANN	Benign	0.80
PhyloP100		-0.28
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs3125001; hg19: chr9-139405261;