rs2229973

Variant names:

• chr9-136500807-G-A
• rs2229973
• NM_017617.5:c.5679C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000651671.1(NOTCH1):​c.5679C>T​(p.Gly1893Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,599,146 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (19 hom.)
• Consequence: NOTCH1 ENST00000651671.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.396
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-136500807-G-A is Benign according to our data. Variant chr9-136500807-G-A is described in ClinVar as Benign. ClinVar VariationId is 241155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.396 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1692/152340) while in subpopulation AFR AF = 0.0368 (1529/41584). AF 95% confidence interval is 0.0352. There are 29 homozygotes in GnomAd4. There are 786 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1692 AD gene.

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.5679C>T	p.Gly1893Gly	synonymous	Exon 31 of 34	NP_060087.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.5679C>T	p.Gly1893Gly	synonymous	Exon 31 of 34	ENSP00000498587.1
	NOTCH1	ENST00000680133.1		c.5565C>T	p.Gly1855Gly	synonymous	Exon 30 of 33	ENSP00000505319.1
	NOTCH1	ENST00000680668.1		c.5565C>T	p.Gly1855Gly	synonymous	Exon 30 of 33	ENSP00000506336.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1678 AN: 152224 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00339 AC: 790 AN: 233148 AF XY: 0.00246

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.00244

Gnomad EAS exome AF: 0.000619

Gnomad FIN exome AF: 0.000398

Gnomad NFE exome AF: 0.000391

Gnomad OTH exome AF: 0.00171

GnomAD4 exome AF: 0.00134 AC: 1933 AN: 1446806 Hom.: 19 Cov.: 32 AF XY: 0.00114 AC XY: 823 AN XY: 720218

African (AFR) AF: 0.0377 AC: 1260 AN: 33448

American (AMR) AF: 0.00441 AC: 197 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26084

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39678

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86192

European-Finnish (FIN) AF: 0.000327 AC: 13 AN: 39760

Middle Eastern (MID) AF: 0.00262 AC: 14 AN: 5336

European-Non Finnish (NFE) AF: 0.000207 AC: 230 AN: 1111466

Other (OTH) AF: 0.00262 AC: 158 AN: 60192

GnomAD4 genome AF: 0.0111 AC: 1692 AN: 152340 Hom.: 29 Cov.: 33 AF XY: 0.0106 AC XY: 786 AN XY: 74498

African (AFR) AF: 0.0368 AC: 1529 AN: 41584

American (AMR) AF: 0.00706 AC: 108 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

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

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68018

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00354 Hom.: 4

Bravo AF: 0.0124

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.80
PhyloP100		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=67/33	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: rs2229973; hg19: chr9-139395259; COSMIC: COSV53038515;