chr9-136502993-G-T

Variant names:

• chr9-136502993-G-T
• rs113377894
• NM_017617.5:c.5167+189C>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.5167+189C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00734 in 820,372 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (160 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (67 hom.)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 1 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-136502993-G-T is Benign according to our data. Variant chr9-136502993-G-T is described in ClinVar as Benign. ClinVar VariationId is 679857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 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.5167+189C>A		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.5167+189C>A		intron	N/A	ENSP00000498587.1
	NOTCH1	ENST00000927794.1		c.5056+189C>A		intron	N/A	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.5053+189C>A		intron	N/A	ENSP00000505319.1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3814 AN: 152128 Hom.: 162 Cov.: 33

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.00552 AC: 745 AN: 134916 AF XY: 0.00420

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00329 AC: 2196 AN: 668126 Hom.: 67 Cov.: 9 AF XY: 0.00269 AC XY: 953 AN XY: 354234

African (AFR) AF: 0.0863 AC: 1556 AN: 18032

American (AMR) AF: 0.00520 AC: 181 AN: 34796

Ashkenazi Jewish (ASJ) AF: 0.0000967 AC: 2 AN: 20688

East Asian (EAS) AF: 0.00 AC: 0 AN: 32478

South Asian (SAS) AF: 0.000498 AC: 32 AN: 64308

European-Finnish (FIN) AF: 0.000421 AC: 14 AN: 33282

Middle Eastern (MID) AF: 0.00439 AC: 19 AN: 4324

European-Non Finnish (NFE) AF: 0.000322 AC: 137 AN: 425768

Other (OTH) AF: 0.00740 AC: 255 AN: 34450

GnomAD4 genome AF: 0.0251 AC: 3828 AN: 152246 Hom.: 160 Cov.: 33 AF XY: 0.0234 AC XY: 1742 AN XY: 74432

African (AFR) AF: 0.0864 AC: 3589 AN: 41532

American (AMR) AF: 0.0105 AC: 161 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.00201 Hom.: 2

Bravo AF: 0.0279

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.13
DANN	Benign	0.62
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs113377894; hg19: chr9-139397445;