rs9356399

chr6-158148854-T-Cchr6-158148854-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032861.4(SERAC1):c.355+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,575,790 control chromosomes in the GnomAD database, including 180,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14960 hom., cov: 33)
  • Exomes 𝑓: 0.48 (165598 hom.)
• Consequence: SERAC1 NM_032861.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.157

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-158148854-T-C is Benign according to our data. Variant chr6-158148854-T-C is described in ClinVar as [Benign]. Clinvar id is 139094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-158148854-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERAC1	NM_032861.4	c.355+11A>G		intron_variant		ENST00000647468.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERAC1	ENST00000647468.2	c.355+11A>G		intron_variant			NM_032861.4	P1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65294 AN: 152044 Hom.: 14933 Cov.: 33

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.481 AC: 117002 AN: 243458 Hom.: 29425 AF XY: 0.479 AC XY: 62984 AN XY: 131464

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.421

Gnomad SAS exome AF: 0.439

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.477

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.478 AC: 679924 AN: 1423628 Hom.: 165598 Cov.: 24 AF XY: 0.478 AC XY: 338929 AN XY: 709540

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.661

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.491

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.430 AC: 65357 AN: 152162 Hom.: 14960 Cov.: 33 AF XY: 0.432 AC XY: 32145 AN XY: 74388

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.518

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.453

Gnomad4 NFE AF: 0.483

Gnomad4 OTH AF: 0.449

Alfa AF: 0.473 Hom.: 8907

Bravo AF: 0.434

Asia WGS AF: 0.417 AC: 1449 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.7
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9356399; hg19: chr6-158569886; COSMIC: COSV65595966;