rs762729988

Variant names:

• chr9-136513063-C-G
• NM_017617.5:c.2425G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-136513063-C-G
• chr9-136513063-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017617.5(NOTCH1):​c.2425G>C​(p.Asp809His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.58

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.2425G>C	p.Asp809His	missense_variant	Exon 15 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.1702G>C	p.Asp568His	missense_variant	Exon 12 of 31		XP_011517019.2
LOC124902310	XR_007061865.1	n.507+3084C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.2425G>C	p.Asp809His	missense_variant	Exon 15 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459154 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.39	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.70
Sift	Benign	0.15	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.60		Loss of ubiquitination at K814 (P = 0.0877);
MVP		0.80
MPC		1.3
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-139407515;