rs869320706

Positions:

• chr7-116771970-CCGAGCTACTTTTCCAGAAGGTATATTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP3

The NM_000245.4(MET):​c.3011_3028+9del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 9.33

Genes affected

MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.033549007 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.3011_3028+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	14/21	ENST00000397752.8
MET	NM_001127500.3	c.3065_3082+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	14/21
MET	NM_001324402.2	c.1721_1738+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/20
MET	XM_011516223.2	c.3068_3085+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.3011_3028+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	14/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.3065_3082+9del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	14/21	1		A2
MET	ENST00000436117.3	c.*616_*633+9del		splice_donor_variant, splice_donor_5th_base_variant, 3_prime_UTR_variant, intron_variant, NMD_transcript_variant	13/20	1
MET	ENST00000454623.1	c.283+318_283+344del		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Osteofibrous dysplasia Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320706; hg19: chr7-116412024;