6-158158205-T-C

Variant names:

• chr6-158158205-T-C
• rs6933016
• NM_032861.4:c.91+68A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032861.4(SERAC1):​c.91+68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,203,186 control chromosomes in the GnomAD database, including 55,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (7674 hom., cov: 31)
  • Exomes 𝑓: 0.29 (47943 hom.)
• Consequence: SERAC1 NM_032861.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0600
• Publications: 6 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: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-158158205-T-C is Benign according to our data. Variant chr6-158158205-T-C is described in ClinVar as Benign. ClinVar VariationId is 671613.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.44 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERAC1	NM_032861.4	MANE Select	c.91+68A>G		intron	N/A	NP_116250.3
	SERAC1	NR_073096.2		n.215+68A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERAC1	ENST00000647468.2	MANE Select	c.91+68A>G		intron	N/A	ENSP00000496731.1
	SERAC1	ENST00000606965.5	TSL:1	n.91+68A>G		intron	N/A	ENSP00000475808.1
	SERAC1	ENST00000607742.5	TSL:1	n.91+68A>G		intron	N/A	ENSP00000475523.1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47184 AN: 151852 Hom.: 7639 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.294

GnomAD4 exome AF: 0.292 AC: 307148 AN: 1051216 Hom.: 47943 AF XY: 0.290 AC XY: 155212 AN XY: 535294

African (AFR) AF: 0.334 AC: 7900 AN: 23688

American (AMR) AF: 0.554 AC: 18278 AN: 33016

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 5227 AN: 21466

East Asian (EAS) AF: 0.492 AC: 17956 AN: 36484

South Asian (SAS) AF: 0.280 AC: 18932 AN: 67576

European-Finnish (FIN) AF: 0.304 AC: 14969 AN: 49304

Middle Eastern (MID) AF: 0.253 AC: 1218 AN: 4810

European-Non Finnish (NFE) AF: 0.273 AC: 209575 AN: 768878

Other (OTH) AF: 0.285 AC: 13093 AN: 45994

GnomAD4 genome AF: 0.311 AC: 47261 AN: 151970 Hom.: 7674 Cov.: 31 AF XY: 0.314 AC XY: 23359 AN XY: 74288

African (AFR) AF: 0.333 AC: 13780 AN: 41436

American (AMR) AF: 0.449 AC: 6858 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3466

East Asian (EAS) AF: 0.425 AC: 2202 AN: 5178

South Asian (SAS) AF: 0.282 AC: 1358 AN: 4810

European-Finnish (FIN) AF: 0.290 AC: 3056 AN: 10552

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18406 AN: 67952

Other (OTH) AF: 0.298 AC: 627 AN: 2104

Alfa AF: 0.299 Hom.: 1014

Bravo AF: 0.325

Asia WGS AF: 0.347 AC: 1203 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		-0.060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6933016; hg19: chr6-158579237; COSMIC: COSV65596653;