rs61751542

Variant names:

• chr9-136505767-G-A
• rs61751542
• NM_017617.5:c.4129C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136505767-G-A
• chr9-136505767-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_017617.5(NOTCH1):​c.4129C>T​(p.Pro1377Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,587,054 control chromosomes in the GnomAD database, including 441 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. P1377L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.020 (403 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:1
• Conservation: PhyloP100: -0.0870
• Publications: 30 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: 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, 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_017617.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0028090775).
• BP6: Variant 9-136505767-G-A is Benign according to our data. Variant chr9-136505767-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

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.4129C>T	p.Pro1377Ser	missense	Exon 25 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.4129C>T	p.Pro1377Ser	missense	Exon 25 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.4018C>T	p.Pro1340Ser	missense	Exon 25 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.4015C>T	p.Pro1339Ser	missense	Exon 24 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2278 AN: 152208 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00388

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0170 AC: 3746 AN: 220252 AF XY: 0.0175

Gnomad AFR exome AF: 0.00398

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0845

Gnomad EAS exome AF: 0.0000589

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0198 AC: 28349 AN: 1434728 Hom.: 403 Cov.: 33 AF XY: 0.0198 AC XY: 14055 AN XY: 710784

African (AFR) AF: 0.00403 AC: 132 AN: 32794

American (AMR) AF: 0.0140 AC: 593 AN: 42258

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 2118 AN: 24784

East Asian (EAS) AF: 0.0000764 AC: 3 AN: 39290

South Asian (SAS) AF: 0.00779 AC: 653 AN: 83830

European-Finnish (FIN) AF: 0.00399 AC: 196 AN: 49142

Middle Eastern (MID) AF: 0.0671 AC: 379 AN: 5648

European-Non Finnish (NFE) AF: 0.0208 AC: 22869 AN: 1097930

Other (OTH) AF: 0.0238 AC: 1406 AN: 59052

GnomAD4 genome AF: 0.0149 AC: 2276 AN: 152326 Hom.: 38 Cov.: 33 AF XY: 0.0146 AC XY: 1086 AN XY: 74482

African (AFR) AF: 0.00387 AC: 161 AN: 41588

American (AMR) AF: 0.0153 AC: 234 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 306 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10624

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1413 AN: 68020

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0258 Hom.: 19

Bravo AF: 0.0169

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00302 AC: 11

ESP6500EA AF: 0.0234 AC: 186

ExAC AF: 0.0158 AC: 1874

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	3	not provided (3)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic valve disease 1 (1)
-	-	1	Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 (1)
1	-	-	Myeloproliferative neoplasm, unclassifiable (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.79
DANN	Benign	0.84
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.33	N
PhyloP100		-0.087
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.32
Sift	Benign	0.59	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.099
MPC		0.38
ClinPred		0.0015	T
GERP RS		-2.5
Varity_R		0.042
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs61751542; hg19: chr9-139400219; COSMIC: COSV53031447; COSMIC: COSV53031447;