rs1553878395

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001410714.1(SEPSECS):​c.1283_1375+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG​(p.Glu428_Leu458del) 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E428E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPSECS NM_001410714.1 splice_donor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.69
• Publications: 1 publications found

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]

SEPSECS Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Broad Center for Mendelian Genomics, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive cerebello-cerebral atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.
• 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 VariationId is 183337.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410714.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	NM_016955.4	MANE Select	c.1028_1120+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG	p.Glu343_Leu373del	splice_donor disruptive_inframe_deletion splice_region intron	Exon 9 of 11	NP_058651.3
	SEPSECS	NM_001410714.1		c.1283_1375+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG	p.Glu428_Leu458del	splice_donor disruptive_inframe_deletion splice_region intron	Exon 10 of 12	NP_001397643.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPSECS	ENST00000382103.7	TSL:1 MANE Select	c.1028_1120+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG	p.Glu343_Leu373del	splice_donor disruptive_inframe_deletion splice_region intron	Exon 9 of 11	ENSP00000371535.2
	SEPSECS	ENST00000358971.7	TSL:1	n.*826_*918+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG		splice_region non_coding_transcript_exon	Exon 10 of 12	ENSP00000351857.3
	SEPSECS	ENST00000514585.5	TSL:1	n.*729_*821+1delAAATGTTTTCATATTTGTCCAACCAAATAAAGAAGTTGTCAGAAGCCTACAATGAAAGACTGTTGCATACACCTCACAATCCCATATCTTTAGG		splice_region non_coding_transcript_exon	Exon 8 of 10	ENSP00000421880.1

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

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebellar ataxia;C0013362:Dysarthria;C0023882:Spastic diplegia;C0027746:Neurodegeneration;C1321325:Elliptical nystagmus;C3509787:Progressive limb weakness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

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

Other links and lift over

dbSNP: rs1553878395; hg19: chr4-25128884;