1-109235430-AGGT-A

Position:

• chr1-109235430-AGGT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP3 PP5

The NM_006513.4(SARS1):​c.969+1_969+3delGTG variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SARS1 NM_006513.4 splice_donor, splice_region, intron
• Clinical Significance: Uncertain significance no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 9.51

Genes affected

SARS1 (HGNC:10537): (seryl-tRNA synthetase 1) This gene belongs to the class II amino-acyl tRNA family. The encoded enzyme catalyzes the transfer of L-serine to tRNA (Ser) and is related to bacterial and yeast counterparts. Multiple alternatively spliced transcript variants have been described but the biological validity of all variants is unknown. [provided by RefSeq, Jul 2010]

SARS1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14304207 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.2, offset of 15, new splice context is: aggGTaagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• PP5: Variant 1-109235430-AGGT-A is Pathogenic according to our data. Variant chr1-109235430-AGGT-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 2443972.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARS1	NM_006513.4	c.969+1_969+3delGTG		splice_donor_variant, splice_region_variant, intron_variant		ENST00000234677.7	NP_006504.2
SARS1	NM_001330669.1	c.969+1_969+3delGTG		splice_donor_variant, splice_region_variant, intron_variant			NP_001317598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SARS1	ENST00000234677.7	c.969+1_969+3delGTG		splice_donor_variant, splice_region_variant, intron_variant		1	NM_006513.4	ENSP00000234677.2
SARS1	ENST00000369923.4	c.969+1_969+3delGTG		splice_donor_variant, splice_region_variant, intron_variant		5		ENSP00000358939.4
SARS1	ENST00000471705.1	n.851_*2delGGT		downstream_gene_variant		2
SARS1	ENST00000477544.5	n.694_*2delGGT		downstream_gene_variant		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: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SARS1-related disorder Pathogenic:1

Pathogenic, flagged submission

research

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Apr 27, 2023

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jun 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 19
DS_DL_spliceai		1.0		Position offset: 1

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: chr1-109778052;