rs183156491

Variant names:

• chr9-136505868-G-A
• rs183156491
• NM_017617.5:c.4028C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136505868-G-A
• chr9-136505868-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_017617.5(NOTCH1):​c.4028C>T​(p.Ala1343Val) variant causes a missense change. The variant allele was found at a frequency of 0.00254 in 1,591,614 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts 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. A1343T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 6.31
• Publications: 29 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2736881).
• BP6: Variant 9-136505868-G-A is Benign according to our data. Variant chr9-136505868-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134932.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 = 0.0017 (259/152308) while in subpopulation NFE AF = 0.00293 (199/68020). AF 95% confidence interval is 0.00259. There are 0 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 259 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.4028C>T	p.Ala1343Val	missense	Exon 25 of 34	NP_060087.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.4028C>T	p.Ala1343Val	missense	Exon 25 of 34	ENSP00000498587.1
	NOTCH1	ENST00000680133.1		c.3914C>T	p.Ala1305Val	missense	Exon 24 of 33	ENSP00000505319.1
	NOTCH1	ENST00000680668.1		c.3914C>T	p.Ala1305Val	missense	Exon 24 of 33	ENSP00000506336.1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00167 AC: 354 AN: 212600 AF XY: 0.00162

Gnomad AFR exome AF: 0.000945

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00263 AC: 3791 AN: 1439306 Hom.: 10 Cov.: 33 AF XY: 0.00249 AC XY: 1784 AN XY: 715710

African (AFR) AF: 0.000569 AC: 19 AN: 33388

American (AMR) AF: 0.00208 AC: 91 AN: 43820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.000164 AC: 14 AN: 85150

European-Finnish (FIN) AF: 0.000214 AC: 8 AN: 37348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00320 AC: 3545 AN: 1109058

Other (OTH) AF: 0.00190 AC: 114 AN: 59886

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74476

African (AFR) AF: 0.000722 AC: 30 AN: 41574

American (AMR) AF: 0.00163 AC: 25 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.00293 AC: 199 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00239 Hom.: 2

Bravo AF: 0.00192

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ExAC AF: 0.00131 AC: 153

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.66	N
PhyloP100		6.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.69
Sift	Benign	0.20	T
Sift4G	Benign	0.31	T
Polyphen		0.94	P
Vest4		0.83
MVP		0.89
MPC		1.1
ClinPred		0.032	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
Mutation Taster		=78/22	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: rs183156491; hg19: chr9-139400320; COSMIC: COSV53082167;