rs11574889

Variant names:

• chr9-136516015-G-A
• rs11574889
• NM_017617.5:c.1635C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136516015-G-A
• chr9-136516015-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017617.5(NOTCH1):​c.1635C>T​(p.Asp545Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,611,970 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (6 hom., cov: 35)
  • Exomes 𝑓: 0.011 (92 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.677
• Publications: 7 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

LOC124902310 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-136516015-G-A is Benign according to our data. Variant chr9-136516015-G-A is described in ClinVar as Benign. ClinVar VariationId is 220907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.677 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0083 (1265/152318) while in subpopulation NFE AF = 0.0128 (870/68014). AF 95% confidence interval is 0.0121. There are 6 homozygotes in GnomAd4. There are 579 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1265 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.1635C>T	p.Asp545Asp	synonymous	Exon 10 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.1635C>T	p.Asp545Asp	synonymous	Exon 10 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.1635C>T	p.Asp545Asp	synonymous	Exon 10 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.1521C>T	p.Asp507Asp	synonymous	Exon 9 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1268 AN: 152200 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00799 AC: 1974 AN: 247150 AF XY: 0.00830

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00583

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.000558

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.0105 AC: 15351 AN: 1459652 Hom.: 92 Cov.: 35 AF XY: 0.0104 AC XY: 7555 AN XY: 726168

African (AFR) AF: 0.00155 AC: 52 AN: 33474

American (AMR) AF: 0.00602 AC: 269 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 426 AN: 26134

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39696

South Asian (SAS) AF: 0.00399 AC: 344 AN: 86248

European-Finnish (FIN) AF: 0.00183 AC: 94 AN: 51492

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5760

European-Non Finnish (NFE) AF: 0.0122 AC: 13510 AN: 1111798

Other (OTH) AF: 0.00943 AC: 569 AN: 60352

GnomAD4 genome AF: 0.00830 AC: 1265 AN: 152318 Hom.: 6 Cov.: 35 AF XY: 0.00777 AC XY: 579 AN XY: 74480

African (AFR) AF: 0.00233 AC: 97 AN: 41576

American (AMR) AF: 0.0105 AC: 160 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0128 AC: 870 AN: 68014

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0106 Hom.: 2

Bravo AF: 0.00841

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0152

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic valve disease 1 (1)
-	-	1	Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.6
DANN	Benign	0.90
PhyloP100		-0.68
Mutation Taster		=98/2	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: rs11574889; hg19: chr9-139410467; COSMIC: COSV53046437; COSMIC: COSV53046437;