rs11574905

chr9-136502974-G-Achr9-136502974-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017617.5(NOTCH1):c.5167+208C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 734,444 control chromosomes in the GnomAD database, including 570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (91 hom., cov: 33)
  • Exomes 𝑓: 0.036 (479 hom.)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.173

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-136502974-G-A is Benign according to our data. Variant chr9-136502974-G-A is described in ClinVar as [Benign]. Clinvar id is 133357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0285 (4345/152230) while in subpopulation NFE AF= 0.0443 (3014/68008). AF 95% confidence interval is 0.043. There are 91 homozygotes in gnomad4. There are 2117 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 4349 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.5167+208C>T		intron_variant		ENST00000651671.1
NOTCH1	XM_011518717.3	c.4444+208C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5167+208C>T		intron_variant			NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4349 AN: 152112 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.00753

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0444

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0275 AC: 3704 AN: 134734 Hom.: 62 AF XY: 0.0274 AC XY: 2013 AN XY: 73378

Gnomad AFR exome AF: 0.00617

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.000285

Gnomad SAS exome AF: 0.00919

Gnomad FIN exome AF: 0.0468

Gnomad NFE exome AF: 0.0465

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0356 AC: 20725 AN: 582214 Hom.: 479 Cov.: 6 AF XY: 0.0344 AC XY: 10773 AN XY: 313150

Gnomad4 AFR exome AF: 0.00787

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.000125

Gnomad4 SAS exome AF: 0.00920

Gnomad4 FIN exome AF: 0.0510

Gnomad4 NFE exome AF: 0.0462

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0285 AC: 4345 AN: 152230 Hom.: 91 Cov.: 33 AF XY: 0.0284 AC XY: 2117 AN XY: 74414

Gnomad4 AFR AF: 0.00751

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0207 Hom.: 14

Bravo AF: 0.0253

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.67
Dann	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs11574905; hg19: chr9-139397426; COSMIC: COSV53026047;