rs11574872

Variant names:

• chr9-136522929-G-A
• rs11574872
• NM_017617.5:c.663C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136522929-G-A
• chr9-136522929-G-T

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.663C>T​(p.Pro221Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,551,300 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (10 hom., cov: 34)
  • Exomes 𝑓: 0.00070 (5 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.659
• 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: 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

LOC124902310 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 9-136522929-G-A is Benign according to our data. Variant chr9-136522929-G-A is described in ClinVar as Benign. ClinVar VariationId is 241162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.659 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00633 (964/152362) while in subpopulation AFR AF = 0.0215 (893/41584). AF 95% confidence interval is 0.0203. There are 10 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 964 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.663C>T	p.Pro221Pro	synonymous	Exon 4 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.663C>T	p.Pro221Pro	synonymous	Exon 4 of 34	ENSP00000498587.1
	NOTCH1	ENST00000927794.1		c.663C>T	p.Pro221Pro	synonymous	Exon 4 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.663C>T	p.Pro221Pro	synonymous	Exon 4 of 33	ENSP00000505319.1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152244 Hom.: 10 Cov.: 34

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00147 AC: 228 AN: 154790 AF XY: 0.00110

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.000918

GnomAD4 exome AF: 0.000699 AC: 978 AN: 1398938 Hom.: 5 Cov.: 31 AF XY: 0.000592 AC XY: 408 AN XY: 689700

African (AFR) AF: 0.0215 AC: 684 AN: 31822

American (AMR) AF: 0.00197 AC: 72 AN: 36526

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 36082

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47062

Middle Eastern (MID) AF: 0.000552 AC: 3 AN: 5430

European-Non Finnish (NFE) AF: 0.000115 AC: 124 AN: 1079234

Other (OTH) AF: 0.00159 AC: 92 AN: 57890

GnomAD4 genome AF: 0.00633 AC: 964 AN: 152362 Hom.: 10 Cov.: 34 AF XY: 0.00579 AC XY: 431 AN XY: 74498

African (AFR) AF: 0.0215 AC: 893 AN: 41584

American (AMR) AF: 0.00333 AC: 51 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00736

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.66
Mutation Taster		=90/10	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: rs11574872; hg19: chr9-139417381; COSMIC: COSV104374307;