6-158111415-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_032861.4(SERAC1):c.1916G>C(p.Arg639Pro) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R639C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERAC1 NM_032861.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 6-158111415-C-G is Pathogenic according to our data. Variant chr6-158111415-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215146.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERAC1	NM_032861.4	c.1916G>C	p.Arg639Pro	missense_variant	17/17	ENST00000647468.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERAC1	ENST00000647468.2	c.1916G>C	p.Arg639Pro	missense_variant	17/17		NM_032861.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2013

p.Arg639Pro (CGT>CCT): c.1916 G>C in exon 17 of the SERAC1 gene (NM_032861.3) A R639P missense change was identified in the SERAC1 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a large, positively charged Arginine is replaced by a small, uncharged Proline with a unique ring structure. This change occurs at a highly conserved position in the SERAC1 protein, and multiple in-silico analysis models predict that R639P is damaging to the SERAC1 protein. Therefore, we interpret R639P to be a pathogenic mutation. The variant is found in MGA-MITOP panel(s). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERAC1 protein function. ClinVar contains an entry for this variant (Variation ID: 215146). This variant has not been reported in the literature in individuals affected with SERAC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 639 of the SERAC1 protein (p.Arg639Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.010	D;.;.;.;.
Sift4G	Benign	0.17	T;.;.;.;.
Polyphen		0.99	D;D;.;.;.
Vest4		0.71
MutPred		0.61		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;.;.;
MVP		0.97
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.95

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: rs768913919; hg19: chr6-158532447;