chr9-136519469-T-G

Position:

• chr9-136519469-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_017617.5(NOTCH1):​c.839A>C​(p.Asn280Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N280S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NOTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.12142703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5	c.839A>C	p.Asn280Thr	missense_variant	5/34	ENST00000651671.1
LOC124902310	XR_007061865.1	n.508-3849T>G		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3	c.116A>C	p.Asn39Thr	missense_variant	2/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1	c.839A>C	p.Asn280Thr	missense_variant	5/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.000280 AC: 69 AN: 246648 Hom.: 0 AF XY: 0.000215 AC XY: 29 AN XY: 134688

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000296

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000233 AC: 34 AN: 1460154 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726366

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: 0.000308

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome Cov.: 34

ExAC AF: 0.00155 AC: 187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.53
Sift	Benign	0.21	T
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.43
MVP		0.82
MPC		1.2
ClinPred		0.052	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45

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: rs367825691; hg19: chr9-139413921;