rs61751543

Variant names:

• chr9-136506781-C-T
• rs61751543
• NM_017617.5:c.3836G>A
• NOTCH1 p.Arg1279His

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017617.5(NOTCH1):​c.3836G>A​(p.Arg1279His) variant causes a missense change. The variant allele was found at a frequency of 0.0225 in 1,609,884 control chromosomes in the GnomAD database, including 495 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1279C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (32 hom., cov: 33)
  • Exomes 𝑓: 0.023 (463 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: 3.60
• Publications: 25 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014274836).
• BP6: Variant 9-136506781-C-T is Benign according to our data. Variant chr9-136506781-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0159 (2426/152312) while in subpopulation NFE AF = 0.0266 (1812/68018). AF 95% confidence interval is 0.0256. There are 32 homozygotes in GnomAd4. There are 1087 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2426 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.3836G>A	p.Arg1279His	missense	Exon 23 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.3836G>A	p.Arg1279His	missense	Exon 23 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.3725G>A	p.Arg1242His	missense	Exon 23 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.3722G>A	p.Arg1241His	missense	Exon 22 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2427 AN: 152194 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0153 AC: 3683 AN: 240694 AF XY: 0.0151

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.00677

Gnomad ASJ exome AF: 0.00629

Gnomad EAS exome AF: 0.000970

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0231 AC: 33719 AN: 1457572 Hom.: 463 Cov.: 34 AF XY: 0.0226 AC XY: 16395 AN XY: 724896

African (AFR) AF: 0.00341 AC: 114 AN: 33396

American (AMR) AF: 0.00780 AC: 346 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00622 AC: 162 AN: 26044

East Asian (EAS) AF: 0.00461 AC: 182 AN: 39504

South Asian (SAS) AF: 0.00490 AC: 420 AN: 85766

European-Finnish (FIN) AF: 0.0199 AC: 1034 AN: 51922

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.0273 AC: 30266 AN: 1110568

Other (OTH) AF: 0.0194 AC: 1171 AN: 60226

GnomAD4 genome AF: 0.0159 AC: 2426 AN: 152312 Hom.: 32 Cov.: 33 AF XY: 0.0146 AC XY: 1087 AN XY: 74478

African (AFR) AF: 0.00411 AC: 171 AN: 41572

American (AMR) AF: 0.00902 AC: 138 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5182

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0266 AC: 1812 AN: 68018

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0262 Hom.: 106

Bravo AF: 0.0148

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	not provided (5)
-	-	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)
-	1	-	Hypoplastic left heart syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.31	N
PhyloP100		3.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.098
Sift	Benign	0.13	T
Sift4G	Benign	0.16	T
Varity_R		0.10
Mutation Taster		=93/7	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs61751543;

hg19: chr9-139401233;

COSMIC: COSV53053047;

COSMIC: COSV53053047;