rs373125283

Variant names:

• chr9-136515675-C-T
• rs373125283
• NM_017617.5:c.1711G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-136515675-C-T
• chr9-136515675-C-A
• chr9-136515675-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_017617.5(NOTCH1):​c.1711G>A​(p.Asp571Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,408,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. D571A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.837
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2845987).
• BS2: High AC in GnomAdExome4 at 24 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.1711G>A	p.Asp571Asn	missense	Exon 11 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.1711G>A	p.Asp571Asn	missense	Exon 11 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000680133.1		c.1597G>A	p.Asp533Asn	missense	Exon 10 of 33	ENSP00000505319.1	A0A7P0T8U6
	NOTCH1	ENST00000680668.1		c.1597G>A	p.Asp533Asn	missense	Exon 10 of 33	ENSP00000506336.1	A0A7P0TB20

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000303 AC: 5 AN: 165150 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000816

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000170 AC: 24 AN: 1408760 Hom.: 0 Cov.: 34 AF XY: 0.0000201 AC XY: 14 AN XY: 697464

African (AFR) AF: 0.00 AC: 0 AN: 32296

American (AMR) AF: 0.0000790 AC: 3 AN: 37954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25498

East Asian (EAS) AF: 0.000108 AC: 4 AN: 37016

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4448

European-Non Finnish (NFE) AF: 0.0000138 AC: 15 AN: 1090576

Other (OTH) AF: 0.00 AC: 0 AN: 58532

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.84
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.22
Sift	Benign	0.40	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.41
MutPred		0.45		Loss of disorder (P = 0.0973)
MVP		0.61
MPC		0.37
ClinPred		0.015	T
GERP RS		4.2
Varity_R		0.025
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373125283; hg19: chr9-139410127;