6-158113439-GAGTGAATACCTGCTGA-CCTGTTGGT

Position:

• chr6-158113439-GAGTGAATACCTGCTGA-CCTGTTGGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032861.4(SERAC1):​c.1822_1828+10delTCAGCAGGTATTCACTCinsACCAACAGG​(p.Ser608fs) variant causes a frameshift, splice donor, splice region, synonymous, 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 (★★). Synonymous variant affecting the same amino acid position (i.e. SAD608?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERAC1 NM_032861.4 frameshift, splice_donor, splice_region, synonymous, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.84

Genes affected

SERAC1 (HGNC:21061): (serine active site containing 1) The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-158113439-GAGTGAATACCTGCTGA-CCTGTTGGT is Pathogenic according to our data. Variant chr6-158113439-GAGTGAATACCTGCTGA-CCTGTTGGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERAC1	NM_032861.4	c.1822_1828+10delTCAGCAGGTATTCACTCinsACCAACAGG	p.Ser608fs	frameshift_variant, splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant	16/17	ENST00000647468.2	NP_116250.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERAC1	ENST00000647468.2	c.1822_1828+10delTCAGCAGGTATTCACTCinsACCAACAGG	p.Ser608fs	frameshift_variant, splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant	16/17		NM_032861.4	ENSP00000496731.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2024	PP4, PM2, PM3_strong, PS4_moderate, PVS1_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 22683713, 27290639, 27331002) -

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 09, 2021	PVS1, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

SERAC1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2022

The SERAC1 c.1822_1828+10delinsACCAACAGG variant is predicted to result in an in-frame deletion and insertion. This variant is predicted to result in frameshift and premature protein termination, however as the deletion/insertion includes the exon 16/intron 16 boundary, this variant is also predicted to abolish the canonical splice donor site based on splicing prediction programs (Alamut Visual v2.11). This variant was reported in homozygous and compound heterozygous states in multiple individuals with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (Wortmann et al. 2012. PubMed ID: 22683713; Pronicka et al. 2016. PubMed ID: 27290639). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

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: rs1554260851; hg19: chr6-158534471;