chr9-136507447-C-T

Variant names:

• chr9-136507447-C-T
• rs139838537
• NM_017617.5:c.3511-10G>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.3511-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,597,334 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (30 hom.)
• Consequence: NOTCH1 NM_017617.5 intron
• Scores: Splicing: ADA: 0.0003089
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.261
• Publications: 2 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 (BayesDel_noAF=-0.85).
• BP6: Variant 9-136507447-C-T is Benign according to our data. Variant chr9-136507447-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 388293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00178 (271/152300) while in subpopulation SAS AF = 0.011 (53/4832). AF 95% confidence interval is 0.00861. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 271 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.3511-10G>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.3511-10G>A		intron	N/A	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.3400-10G>A		intron	N/A	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.3397-10G>A		intron	N/A	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152182 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00334 AC: 713 AN: 213328 AF XY: 0.00401

Gnomad AFR exome AF: 0.000158

Gnomad AMR exome AF: 0.000965

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.000190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00568

GnomAD4 exome AF: 0.00209 AC: 3026 AN: 1445034 Hom.: 30 Cov.: 33 AF XY: 0.00243 AC XY: 1744 AN XY: 717480

African (AFR) AF: 0.000210 AC: 7 AN: 33350

American (AMR) AF: 0.00114 AC: 47 AN: 41400

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 285 AN: 25708

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39036

South Asian (SAS) AF: 0.0118 AC: 990 AN: 84022

European-Finnish (FIN) AF: 0.0000394 AC: 2 AN: 50758

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5740

European-Non Finnish (NFE) AF: 0.00132 AC: 1462 AN: 1105284

Other (OTH) AF: 0.00280 AC: 167 AN: 59736

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152300 Hom.: 0 Cov.: 34 AF XY: 0.00201 AC XY: 150 AN XY: 74478

African (AFR) AF: 0.000265 AC: 11 AN: 41562

American (AMR) AF: 0.000979 AC: 15 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00170

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	1	Aortic valve disease 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.60
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.0040
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: rs139838537; hg19: chr9-139401899;