rs1553878395

Variant names:

• chr4-25127262-ACCTAAAGATATGGGATTGTGAGGTGTATGCAACAGTCTTTCATTGTAGGCTTCTGACAACTTCTTTATTTGGTTGGACAAATATGAAAACATTT-A
• rs1553878395
• NM_016955.4:c.1028_1120+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016955.4(SEPSECS):​c.1028_1120+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG​(p.Glu343_Leu373del) variant causes a splice donor, disruptive inframe deletion, splice region, 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPSECS NM_016955.4 splice_donor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.69

Genes affected

SEPSECS (HGNC:30605): (Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase) The amino acid selenocysteine is the only amino acid that does not have its own tRNA synthetase. Instead, this amino acid is synthesized on its cognate tRNA in a three step process. The protein encoded by this gene catalyzes the third step in the process, the conversion of O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec).[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-25127262-ACCTAAAGATATGGGATTGTGAGGTGTATGCAACAGTCTTTCATTGTAGGCTTCTGACAACTTCTTTATTTGGTTGGACAAATATGAAAACATTT-A is Pathogenic according to our data. Variant chr4-25127262-ACCTAAAGATATGGGATTGTGAGGTGTATGCAACAGTCTTTCATTGTAGGCTTCTGACAACTTCTTTATTTGGTTGGACAAATATGAAAACATTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183337.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPSECS	NM_016955.4	c.1028_1120+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG	p.Glu343_Leu373del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 9 of 11	ENST00000382103.7	NP_058651.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPSECS	ENST00000382103.7	c.1028_1120+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG	p.Glu343_Leu373del	splice_donor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 9 of 11	1	NM_016955.4	ENSP00000371535.2

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebellar ataxia;C0013362:Dysarthria;C0023882:Spastic diplegia;C0027746:Neurodegeneration;C1321325:Elliptical nystagmus;C3509787:Progressive limb weakness Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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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: rs1553878395; hg19: chr4-25128884;