rs11574911

Variant names:

• chr9-136496506-T-C
• rs11574911
• NM_017617.5:c.7233A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-136496506-T-C
• chr9-136496506-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000651671.1(NOTCH1):​c.7233A>G​(p.Pro2411Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,602,606 control chromosomes in the GnomAD database, including 334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (176 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (158 hom.)
• Consequence: NOTCH1 ENST00000651671.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.610
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136496506-T-C is Benign according to our data. Variant chr9-136496506-T-C is described in ClinVar as Benign. ClinVar VariationId is 285559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0863 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000651671.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	NM_017617.5	MANE Select	c.7233A>G	p.Pro2411Pro	synonymous	Exon 34 of 34	NP_060087.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.7233A>G	p.Pro2411Pro	synonymous	Exon 34 of 34	ENSP00000498587.1
	NOTCH1	ENST00000680133.1		c.7119A>G	p.Pro2373Pro	synonymous	Exon 33 of 33	ENSP00000505319.1
	NOTCH1	ENST00000680668.1		c.7119A>G	p.Pro2373Pro	synonymous	Exon 33 of 33	ENSP00000506336.1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4037 AN: 152200 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.00758 AC: 1793 AN: 236620 AF XY: 0.00577

Gnomad AFR exome AF: 0.0913

Gnomad AMR exome AF: 0.00608

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000726

Gnomad NFE exome AF: 0.000803

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00335 AC: 4856 AN: 1450288 Hom.: 158 Cov.: 31 AF XY: 0.00295 AC XY: 2128 AN XY: 721844

African (AFR) AF: 0.0912 AC: 3054 AN: 33472

American (AMR) AF: 0.00707 AC: 316 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 323 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86256

European-Finnish (FIN) AF: 0.000237 AC: 10 AN: 42164

Middle Eastern (MID) AF: 0.00800 AC: 46 AN: 5750

European-Non Finnish (NFE) AF: 0.000555 AC: 617 AN: 1111846

Other (OTH) AF: 0.00778 AC: 469 AN: 60268

GnomAD4 genome AF: 0.0266 AC: 4059 AN: 152318 Hom.: 176 Cov.: 33 AF XY: 0.0259 AC XY: 1929 AN XY: 74484

African (AFR) AF: 0.0887 AC: 3688 AN: 41566

American (AMR) AF: 0.0147 AC: 225 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68024

Other (OTH) AF: 0.0227 AC: 48 AN: 2112

Alfa AF: 0.0130 Hom.: 21

Bravo AF: 0.0306

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.082
DANN	Benign	0.32
PhyloP100		-0.61
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: rs11574911; hg19: chr9-139390958; COSMIC: COSV53037551;