rs61751539

Variant names:

• chr9-136504804-G-A
• rs61751539
• NM_017617.5:c.4887C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136504804-G-A
• chr9-136504804-G-C
• chr9-136504804-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.4887C>T​(p.His1629His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,562,334 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.05
• Publications: 0 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: 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-136504804-G-A is Benign according to our data. Variant chr9-136504804-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/152358) while in subpopulation NFE AF = 0.00291 (198/68024). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 271 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.4887C>T	p.His1629His	synonymous	Exon 26 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.4887C>T	p.His1629His	synonymous	Exon 26 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.4776C>T	p.His1592His	synonymous	Exon 26 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.4773C>T	p.His1591His	synonymous	Exon 25 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00163 AC: 274 AN: 168040 AF XY: 0.00145

Gnomad AFR exome AF: 0.000655

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00128

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000321

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00262 AC: 3692 AN: 1409976 Hom.: 8 Cov.: 33 AF XY: 0.00251 AC XY: 1748 AN XY: 696602

African (AFR) AF: 0.000400 AC: 13 AN: 32492

American (AMR) AF: 0.00143 AC: 53 AN: 36940

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 32 AN: 25252

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37164

South Asian (SAS) AF: 0.000300 AC: 24 AN: 80126

European-Finnish (FIN) AF: 0.000228 AC: 11 AN: 48236

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5664

European-Non Finnish (NFE) AF: 0.00315 AC: 3422 AN: 1085652

Other (OTH) AF: 0.00222 AC: 130 AN: 58450

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00156 AC XY: 116 AN XY: 74516

African (AFR) AF: 0.000746 AC: 31 AN: 41582

American (AMR) AF: 0.00202 AC: 31 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00186

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic valve disease 1 (1)
-	-	1	Connective tissue disorder (1)
-	-	1	not specified (1)
-	-	1	NOTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.82
DANN	Benign	0.53
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs61751539; hg19: chr9-139399256;