rs954507677

Variant names:

• chr9-136505625-A-G
• rs954507677
• NM_017617.5:c.4271T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-136505625-A-G
• chr9-136505625-A-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.4271T>C​(p.Leu1424Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1424L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 1.05
• Publications: 1 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=0.31265655).
• BP6: Variant 9-136505625-A-G is Benign according to our data. Variant chr9-136505625-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 544188.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000011 (16/1459864) while in subpopulation MID AF = 0.000694 (4/5766). AF 95% confidence interval is 0.000236. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 16 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.4271T>C	p.Leu1424Ser	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.4271T>C	p.Leu1424Ser	missense	Exon 25 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.4160T>C	p.Leu1387Ser	missense	Exon 25 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.4157T>C	p.Leu1386Ser	missense	Exon 24 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245798 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459864 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 726192

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52042

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111596

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000563 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Adams-Oliver syndrome 5 (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)
-	-	-	Aortic valve disorder;C4014970:Adams-Oliver syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.087
Sift	Benign	0.40	T
Sift4G	Benign	0.38	T
Polyphen		0.040	B
Vest4		0.47
MutPred		0.55		Loss of ubiquitination at K1419 (P = 0.0997)
MVP		0.66
MPC		0.58
ClinPred		0.058	T
GERP RS		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
Mutation Taster		=92/8	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: rs954507677; hg19: chr9-139400077; COSMIC: COSV53051121; COSMIC: COSV53051121;