9-136508242-C-T

Variant names:

• chr9-136508242-C-T
• rs3812602
• NM_017617.5:c.3315G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017617.5(NOTCH1):​c.3315G>A​(p.Ala1105Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00005 in 1,459,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1105A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.29
• Publications: 6 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-136508242-C-T is Benign according to our data. Variant chr9-136508242-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1147485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.29 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 73 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.3315G>A	p.Ala1105Ala	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.3315G>A	p.Ala1105Ala	synonymous	Exon 20 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.3204G>A	p.Ala1068Ala	synonymous	Exon 20 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.3201G>A	p.Ala1067Ala	synonymous	Exon 19 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000284 AC: 7 AN: 246598 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1459394 Hom.: 0 Cov.: 39 AF XY: 0.0000565 AC XY: 41 AN XY: 725966

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39668

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111436

Other (OTH) AF: 0.0000829 AC: 5 AN: 60332

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000265 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.037
DANN	Benign	0.52
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3812602; hg19: chr9-139402694;