rs111627256

Variant names:

• chr9-136496133-C-T
• rs111627256
• NM_017617.5:c.7606G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-136496133-C-T
• chr9-136496133-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017617.5(NOTCH1):​c.7606G>A​(p.Val2536Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,609,464 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. V2536V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.72
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04889512).
• BP6: Variant 9-136496133-C-T is Benign according to our data. Variant chr9-136496133-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477975.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000578 (88/152212) while in subpopulation AFR AF = 0.00125 (52/41538). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.7606G>A	p.Val2536Ile	missense	Exon 34 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.7606G>A	p.Val2536Ile	missense	Exon 34 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.7495G>A	p.Val2499Ile	missense	Exon 34 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.7492G>A	p.Val2498Ile	missense	Exon 33 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000364 AC: 87 AN: 238910 AF XY: 0.000354

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000481

Gnomad OTH exome AF: 0.000350

GnomAD4 exome AF: 0.000243 AC: 354 AN: 1457252 Hom.: 2 Cov.: 31 AF XY: 0.000247 AC XY: 179 AN XY: 724592

African (AFR) AF: 0.00117 AC: 39 AN: 33472

American (AMR) AF: 0.000270 AC: 12 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25844

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39612

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51316

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.000238 AC: 265 AN: 1111370

Other (OTH) AF: 0.000448 AC: 27 AN: 60230

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74422

African (AFR) AF: 0.00125 AC: 52 AN: 41538

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000570 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000502 AC: 2

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.000334 AC: 40

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	7.4
DANN	Benign	0.48
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.65
MVP		0.81
MPC		0.29
ClinPred		0.00094	T
GERP RS		0.94
Varity_R		0.022
Mutation Taster		=95/5	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: rs111627256; hg19: chr9-139390585;