Genetic Variant SERAC1:c.487+748T>A (chr6-158146034-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032861.4(SERAC1):c.487+748T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,262 control chromosomes in the GnomAD database, including 2,504 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2504 hom., cov: 32)

Exomes 𝑓: 0.25 ( 0 hom. )

Consequence

SERAC1
NM_032861.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

SERAC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERAC1	NM_032861.4 link	c.487+748T>A		intron_variant	Intron 6 of 16	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.487+748T>A		intron_variant	Intron 6 of 16		NM_032861.4	ENSP00000496731.1		Q96JX3-1

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21937

AN:

152140

Hom.:

2484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0353

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.350

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.424

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.202

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.148

GnomAD4 exome

AF:

0.250

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.144

AC:

21971

AN:

152258

Hom.:

2504

Cov.:

AF XY:

0.152

AC XY:

11290

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0352

AC:

1462

AN:

41576

American (AMR)

AF:

0.352

AC:

5372

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

375

AN:

3470

East Asian (EAS)

AF:

0.424

AC:

2197

AN:

5184

South Asian (SAS)

AF:

0.167

AC:

808

AN:

4832

European-Finnish (FIN)

AF:

0.202

AC:

2135

AN:

10580

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9225

AN:

68020

Other (OTH)

AF:

0.152

AC:

320

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

902

1805

2707

3610

4512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0574

Hom.:

Bravo

AF:

0.154

Asia WGS

AF:

0.270

AC:

934

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

6.0

(source)

DANN

Benign

0.65

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over