Genetic Variant NM_032861.4:c.1846C>A (chr6-158111485-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SERAC1
NM_032861.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.26

Variant links:

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]

SERAC1 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SERAC1	NM_032861.4 link	c.1846C>A	p.Leu616Ile	missense_variant	Exon 17 of 17	ENST00000647468.2	NP_116250.3	Q96JX3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERAC1	ENST00000647468.2 link	c.1846C>A	p.Leu616Ile	missense_variant	Exon 17 of 17		NM_032861.4	ENSP00000496731.1		Q96JX3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

235488

Hom.:

AF XY:

0.00000783

AC XY:

AN XY:

127676

show subpopulations

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:

AN:

1446792

Hom.:

Cov.:

AF XY:

0.00000973

AC XY:

AN XY:

719494

show subpopulations

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.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

May 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0081

T;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

.;T;T;T;T

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.6

M;M;.;.;.

PrimateAI

Uncertain

0.65

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over