rs3124607

chr9-136520387-G-Achr9-136520387-G-Cchr9-136520387-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017617.5(NOTCH1):c.743-822C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 151,878 control chromosomes in the GnomAD database, including 14,300 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14300 hom., cov: 32)
• Consequence: NOTCH1 NM_017617.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113

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]

LOC124902310 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.743-822C>T		intron_variant		ENST00000651671.1
LOC124902310	XR_007061865.1	n.508-2931G>A		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.20-822C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.743-822C>T		intron_variant			NM_017617.5	P1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63213 AN: 151760 Hom.: 14287 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.363

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63268 AN: 151878 Hom.: 14300 Cov.: 32 AF XY: 0.426 AC XY: 31609 AN XY: 74198

Gnomad4 AFR AF: 0.496

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.864

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.492

Gnomad4 NFE AF: 0.326

Gnomad4 OTH AF: 0.366

Alfa AF: 0.338 Hom.: 13176

Bravo AF: 0.423

Asia WGS AF: 0.611 AC: 2121 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.7
Dann	Benign	0.56

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: rs3124607; hg19: chr9-139414839;