rs61751557

Variant names:

• chr9-136522881-G-A
• rs61751557
• NM_017617.5:c.711C>T
• NOTCH1 p.Gly237Gly

Variant summary

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

The NM_017617.5(NOTCH1):​c.711C>T​(p.Gly237Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,524,882 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (97 hom., cov: 34)
  • Exomes 𝑓: 0.0020 (65 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.50
• Publications: 3 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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

LOC124902310 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-136522881-G-A is Benign according to our data. Variant chr9-136522881-G-A is described in ClinVar as Benign. ClinVar VariationId is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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.711C>T	p.Gly237Gly	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.711C>T	p.Gly237Gly	synonymous	Exon 4 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.711C>T	p.Gly237Gly	synonymous	Exon 4 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.711C>T	p.Gly237Gly	synonymous	Exon 4 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2618 AN: 152248 Hom.: 97 Cov.: 34

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00529 AC: 718 AN: 135800 AF XY: 0.00424

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.00899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00302

GnomAD4 exome AF: 0.00202 AC: 2778 AN: 1372516 Hom.: 65 Cov.: 31 AF XY: 0.00179 AC XY: 1208 AN XY: 673826

African (AFR) AF: 0.0637 AC: 1991 AN: 31248

American (AMR) AF: 0.00838 AC: 296 AN: 35312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23956

East Asian (EAS) AF: 0.00 AC: 0 AN: 35598

South Asian (SAS) AF: 0.000469 AC: 36 AN: 76810

European-Finnish (FIN) AF: 0.0000241 AC: 1 AN: 41574

Middle Eastern (MID) AF: 0.00474 AC: 21 AN: 4434

European-Non Finnish (NFE) AF: 0.000192 AC: 205 AN: 1066750

Other (OTH) AF: 0.00401 AC: 228 AN: 56834

GnomAD4 genome AF: 0.0172 AC: 2621 AN: 152366 Hom.: 97 Cov.: 34 AF XY: 0.0166 AC XY: 1234 AN XY: 74514

African (AFR) AF: 0.0593 AC: 2464 AN: 41586

American (AMR) AF: 0.00712 AC: 109 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68026

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00820 Hom.: 4

Bravo AF: 0.0197

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Adams-Oliver syndrome 5 (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	-0.63
CADD	Benign	1.5
DANN	Benign	0.80
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61751557;

hg19: chr9-139417333;

COSMIC: COSV53037665;

COSMIC: COSV53037665;