rs201620358

Variant names:

• chr9-136510659-G-A
• rs201620358
• NM_017617.5:c.2734C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136510659-G-A
• chr9-136510659-G-C
• chr9-136510659-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.2734C>T​(p.Arg912Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,605,840 control chromosomes in the GnomAD database, including 8 homozygotes. 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. R912Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:13 O:1
• Conservation: PhyloP100: 2.57
• Publications: 32 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

LOC124902310 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105588555).
• BP6: Variant 9-136510659-G-A is Benign according to our data. Variant chr9-136510659-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134921.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00219 (333/152362) while in subpopulation NFE AF = 0.00345 (235/68028). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 333 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.2734C>T	p.Arg912Trp	missense	Exon 17 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.2734C>T	p.Arg912Trp	missense	Exon 17 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.2623C>T	p.Arg875Trp	missense	Exon 17 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.2620C>T	p.Arg874Trp	missense	Exon 16 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00170 AC: 394 AN: 231904 AF XY: 0.00161

Gnomad AFR exome AF: 0.000562

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.000513

Gnomad EAS exome AF: 0.000172

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00265 AC: 3857 AN: 1453478 Hom.: 8 Cov.: 32 AF XY: 0.00251 AC XY: 1816 AN XY: 723180

African (AFR) AF: 0.000329 AC: 11 AN: 33418

American (AMR) AF: 0.00189 AC: 84 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.000691 AC: 18 AN: 26046

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39532

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85868

European-Finnish (FIN) AF: 0.00233 AC: 111 AN: 47610

Middle Eastern (MID) AF: 0.00107 AC: 6 AN: 5582

European-Non Finnish (NFE) AF: 0.00313 AC: 3476 AN: 1110838

Other (OTH) AF: 0.00225 AC: 135 AN: 60126

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152362 Hom.: 0 Cov.: 34 AF XY: 0.00204 AC XY: 152 AN XY: 74502

African (AFR) AF: 0.000625 AC: 26 AN: 41596

American (AMR) AF: 0.00294 AC: 45 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00345 AC: 235 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00215

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000495 AC: 2

ESP6500EA AF: 0.00324 AC: 27

ExAC AF: 0.00163 AC: 196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	not provided (8)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	1	2	not specified (4)
-	-	1	Adams-Oliver syndrome 5 (1)
-	-	1	Aortic valve disease 1 (1)
-	1	-	Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 (1)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.96	L
PhyloP100		2.6
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.74
MPC		1.0
ClinPred		0.032	T
GERP RS		2.9
Varity_R		0.14
Mutation Taster		=80/20	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: rs201620358; hg19: chr9-139405111; COSMIC: COSV53040452;