6-158158343-G-T

Variant names:

• chr6-158158343-G-T
• rs139301835
• NM_032861.4:c.21C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032861.4(SERAC1):​c.21C>A​(p.Cys7*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C7C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERAC1 NM_032861.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.132

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 54 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-158158343-G-T is Pathogenic according to our data. Variant chr6-158158343-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505907.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERAC1	NM_032861.4	c.21C>A	p.Cys7*	stop_gained	Exon 2 of 17	ENST00000647468.2	NP_116250.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERAC1	ENST00000647468.2	c.21C>A	p.Cys7*	stop_gained	Exon 2 of 17		NM_032861.4	ENSP00000496731.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial oxidative phosphorylation disorder Pathogenic:1

Jul 11, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys7X (NM_032861.3 c.21C>A) variant in SERAC1 has not been previously repo rted in the literature and was absent from large population studies. This nonsen se variant leads to a premature termination codon at position 7, which is predic ted to lead to a truncated or absent protein. Biallelic loss of function of the SERAC1 gene has been associated with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome), also referred to as 3-methylglutaconic aciduria type VI (MGCA6). In summary, although additional stu dies are required to fully establish a null effect on the protein, the p.Cys7X v ariant in the SERAC1 gene is likely pathogenic for MEGDEL syndrome in an autosom al recessive manner based on its predicted impact on the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.16	N
Vest4		0.29
GERP RS		-0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139301835; hg19: chr6-158579375;