6-158146034-A-T

Variant names:

• chr6-158146034-A-T
• rs9295316
• NM_032861.4:c.487+748T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032861.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERAC1	NM_032861.4	MANE Select	c.487+748T>A		intron	N/A	NP_116250.3
	SERAC1	NR_073096.2		n.611+748T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERAC1	ENST00000647468.2	MANE Select	c.487+748T>A		intron	N/A	ENSP00000496731.1	Q96JX3-1
	SERAC1	ENST00000606965.5	TSL:1	n.487+748T>A		intron	N/A	ENSP00000475808.1	U3KQE4
	SERAC1	ENST00000607742.5	TSL:1	n.*321+748T>A		intron	N/A	ENSP00000475523.1	U3KQG3

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21937 AN: 152140 Hom.: 2484 Cov.: 32

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: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ 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.

GnomAD4 genome AF: 0.144 AC: 21971 AN: 152258 Hom.: 2504 Cov.: 32 AF XY: 0.152 AC XY: 11290 AN XY: 74442

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: 25 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9225 AN: 68020

Other (OTH) AF: 0.152 AC: 320 AN: 2110

Alfa AF: 0.0574 Hom.: 79

Bravo AF: 0.154

Asia WGS AF: 0.270 AC: 934 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.65
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9295316; hg19: chr6-158567066;