rs182330532

Variant names:

• chr9-136506782-G-A
• rs182330532
• NM_017617.5:c.3835C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136506782-G-A
• chr9-136506782-G-C
• chr9-136506782-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.3835C>T​(p.Arg1279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,610,112 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1279H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 9.54
• Publications: 22 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41389948).
• BP6: Variant 9-136506782-G-A is Benign according to our data. Variant chr9-136506782-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241139.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000578 (88/152324) while in subpopulation NFE AF = 0.000956 (65/68026). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 88 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.3835C>T	p.Arg1279Cys	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.3835C>T	p.Arg1279Cys	missense	Exon 23 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.3724C>T	p.Arg1242Cys	missense	Exon 23 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.3721C>T	p.Arg1241Cys	missense	Exon 22 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152206 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000370 AC: 89 AN: 240610 AF XY: 0.000381

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00182

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000562

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000766 AC: 1116 AN: 1457788 Hom.: 0 Cov.: 34 AF XY: 0.000767 AC XY: 556 AN XY: 725022

African (AFR) AF: 0.000120 AC: 4 AN: 33394

American (AMR) AF: 0.000270 AC: 12 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 44 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 85792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000912 AC: 1013 AN: 1110744

Other (OTH) AF: 0.000714 AC: 43 AN: 60218

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152324 Hom.: 0 Cov.: 34 AF XY: 0.000470 AC XY: 35 AN XY: 74482

African (AFR) AF: 0.000289 AC: 12 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000690 Hom.: 4

Bravo AF: 0.000555

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.000944 AC: 8

ExAC AF: 0.000240 AC: 29

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Adams-Oliver syndrome 5 (1)
-	-	1	Neurofibromatosis, type 1 (1)
-	-	1	not specified (1)
-	-	1	NOTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.44
Sift	Benign	0.032	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.73
MVP		0.78
MPC		1.2
ClinPred		0.40	T
GERP RS		5.1
Varity_R		0.21
Mutation Taster		=71/29	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: rs182330532; hg19: chr9-139401234; COSMIC: COSV53047136;