6-158111485-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032861.4(SERAC1):c.1846C>A(p.Leu616Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,446,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L616L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SERAC1 NM_032861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24598983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERAC1	NM_032861.4	c.1846C>A	p.Leu616Ile	missense_variant	17/17	ENST00000647468.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERAC1	ENST00000647468.2	c.1846C>A	p.Leu616Ile	missense_variant	17/17		NM_032861.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000170 AC: 4 AN: 235488 Hom.: 0 AF XY: 0.00000783 AC XY: 1 AN XY: 127676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1446792 Hom.: 0 Cov.: 28 AF XY: 0.00000973 AC XY: 7 AN XY: 719494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 10, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERAC1 protein function. ClinVar contains an entry for this variant (Variation ID: 1413327). This variant has not been reported in the literature in individuals affected with SERAC1-related conditions. This variant is present in population databases (rs780572089, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 616 of the SERAC1 protein (p.Leu616Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0081	T;T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	M;M;.;.;.
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.81	N;.;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.035	D;.;.;.;.
Sift4G	Benign	0.18	T;.;.;.;.
Polyphen		0.29	B;B;.;.;.
Vest4		0.38
MutPred		0.43		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;
MVP		0.61
MPC		0.29
ClinPred		0.40	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs780572089; hg19: chr6-158532517;