rs139994842

Variant names:

• chr9-136508308-G-A
• rs139994842
• NM_017617.5:c.3249C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136508308-G-A
• chr9-136508308-G-C
• chr9-136508308-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.3249C>T​(p.Cys1083Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,612,984 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00040 (10 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.23
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-136508308-G-A is Benign according to our data. Variant chr9-136508308-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000696 (106/152336) while in subpopulation EAS AF = 0.0177 (92/5184). AF 95% confidence interval is 0.0148. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 106 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.3249C>T	p.Cys1083Cys	synonymous	Exon 20 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.3249C>T	p.Cys1083Cys	synonymous	Exon 20 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.3138C>T	p.Cys1046Cys	synonymous	Exon 20 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.3135C>T	p.Cys1045Cys	synonymous	Exon 19 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152218 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00147 AC: 365 AN: 248242 AF XY: 0.00144

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000403 AC: 588 AN: 1460648 Hom.: 10 Cov.: 39 AF XY: 0.000403 AC XY: 293 AN XY: 726628

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00940 AC: 373 AN: 39696

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52246

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111976

Other (OTH) AF: 0.00277 AC: 167 AN: 60380

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152336 Hom.: 1 Cov.: 34 AF XY: 0.000631 AC XY: 47 AN XY: 74486

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0177 AC: 92 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000227 Hom.: 1

Bravo AF: 0.000725

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.7
DANN	Benign	0.63
PhyloP100		-1.2
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139994842; hg19: chr9-139402760; COSMIC: COSV53025422; COSMIC: COSV53025422;