rs61751548

Variant names:

• chr9-136510729-G-A
• rs61751548
• NM_017617.5:c.2664C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136510729-G-A
• chr9-136510729-G-C

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.2664C>T​(p.His888His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,610,620 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 34)
  • Exomes 𝑓: 0.017 (211 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.474
• 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: 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

LOC124902310 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-136510729-G-A is Benign according to our data. Variant chr9-136510729-G-A is described in ClinVar as Benign. ClinVar VariationId is 220987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.474 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1715/152350) while in subpopulation NFE AF = 0.0182 (1238/68022). AF 95% confidence interval is 0.0174. There are 13 homozygotes in GnomAd4. There are 761 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1715 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	NM_017617.5	MANE Select	c.2664C>T	p.His888His	synonymous	Exon 17 of 34	NP_060087.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.2664C>T	p.His888His	synonymous	Exon 17 of 34	ENSP00000498587.1
	NOTCH1	ENST00000680133.1		c.2550C>T	p.His850His	synonymous	Exon 16 of 33	ENSP00000505319.1
	NOTCH1	ENST00000680668.1		c.2550C>T	p.His850His	synonymous	Exon 16 of 33	ENSP00000506336.1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1715 AN: 152232 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0125 AC: 3013 AN: 241638 AF XY: 0.0125

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.00938

Gnomad ASJ exome AF: 0.00911

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00764

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0167 AC: 24341 AN: 1458270 Hom.: 211 Cov.: 32 AF XY: 0.0163 AC XY: 11853 AN XY: 725642

African (AFR) AF: 0.00272 AC: 91 AN: 33468

American (AMR) AF: 0.00953 AC: 426 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00984 AC: 257 AN: 26108

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39684

South Asian (SAS) AF: 0.00304 AC: 262 AN: 86240

European-Finnish (FIN) AF: 0.0105 AC: 529 AN: 50266

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5762

European-Non Finnish (NFE) AF: 0.0196 AC: 21840 AN: 1111760

Other (OTH) AF: 0.0148 AC: 892 AN: 60288

GnomAD4 genome AF: 0.0113 AC: 1715 AN: 152350 Hom.: 13 Cov.: 34 AF XY: 0.0102 AC XY: 761 AN XY: 74498

African (AFR) AF: 0.00310 AC: 129 AN: 41598

American (AMR) AF: 0.0114 AC: 175 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1238 AN: 68022

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0164 Hom.: 6

Bravo AF: 0.0120

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0208

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	1	Aortic valve disease 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.32
DANN	Benign	0.94
PhyloP100		-0.47
Mutation Taster		=99/1	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: rs61751548; hg19: chr9-139405181;