6-158111108-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_032861.4(SERAC1):c.*258G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 259,010 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: SERAC1 NM_032861.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.372

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-158111108-C-T is Benign according to our data. Variant chr6-158111108-C-T is described in ClinVar as [Benign]. Clinvar id is 2500852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERAC1	NM_032861.4	c.*258G>A		3_prime_UTR_variant	17/17	ENST00000647468.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERAC1	ENST00000647468.2	c.*258G>A		3_prime_UTR_variant	17/17		NM_032861.4	P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152186 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00100 AC: 107 AN: 106706 Hom.: 1 Cov.: 2 AF XY: 0.000940 AC XY: 51 AN XY: 54250

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000420

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152304 Hom.: 3 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74456

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0198

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome Benign:1

Benign, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The heterozygous c.*258G>A variant in SERAC1 was identified by our study, in the compound heterozygous state, along with a likely pathogenic variant (ClinVar Variation ID: 938842), in one individual with neonatal 3-methylglutaconic aciduria, muscular spasticity, and multi-organ insufficiency. Trio exome analysis revealed this variant to be in trans with a likely pathogenic variant (ClinVar Variation ID: 938842). The c.*258G>A variant in SERAC1 has not been previously reported in individuals with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome but has been identified in 2% (210/10606) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs185841896). This variant was detected in 3 control individuals of the European (Finnish) population by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs185841896), suggesting that this variant is not pathogenic for 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.*258G>A variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM3, BS1, BS2, BP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.1
Dann	Benign	0.32

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: rs185841896; hg19: chr6-158532140;