6-158113439-GAGTGAATACCTGCTGA-CCTGTTGGT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_032861.4(SERAC1):c.1822_1828+10delinsACCAACAGG 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. SAD608?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERAC1 NM_032861.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 13 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.07277354 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -11, new splice context is: gtgGTacct. Cryptic site results in frameshift 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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	UniProt
SERAC1	NM_032861.4	c.1822_1828+10delinsACCAACAGG		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	16/17	ENST00000647468.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERAC1	ENST00000647468.2	c.1822_1828+10delinsACCAACAGG		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	16/17		NM_032861.4	P1

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: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not provided Pathogenic:1

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) -

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;