rs371575191

Variant names:

• chr9-136496069-G-A
• rs371575191
• NM_017617.5:c.*2C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136496069-G-A
• chr9-136496069-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017617.5(NOTCH1):​c.*2C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,599,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.844
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-136496069-G-A is Benign according to our data. Variant chr9-136496069-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1216624.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000193 (279/1447234) while in subpopulation NFE AF = 0.000242 (269/1110066). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAdExome4. There are 144 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.*2C>T		3_prime_UTR_variant	Exon 34 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.*2C>T		3_prime_UTR_variant	Exon 31 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.*2C>T		3_prime_UTR_variant	Exon 34 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152196 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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000574 AC: 13 AN: 226382 AF XY: 0.0000484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000589

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000193 AC: 279 AN: 1447234 Hom.: 0 Cov.: 31 AF XY: 0.000200 AC XY: 144 AN XY: 719314

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39444

South Asian (SAS) AF: 0.00 AC: 0 AN: 84454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000242 AC: 269 AN: 1110066

Other (OTH) AF: 0.000133 AC: 8 AN: 60100

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.0000793

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 22, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.87
PhyloP100		0.84

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: rs371575191; hg19: chr9-139390521; COSMIC: COSV99490133;