NM_032861.4:c.1963_*1delTAAC

Variant names:

• chr6-158111364-TGTTA-T
• NM_032861.4:c.1963_*1delTAAC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_032861.4(SERAC1):​c.1963_*1delTAAC​(p.Ter655fs) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERAC1 NM_032861.4 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15
• Publications: 0 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

ENSG00000306953 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1963_*1delTAAC	p.Ter655fs	frameshift stop_lost	Exon 17 of 17	NP_116250.3
	SERAC1	NM_032861.4	MANE Select	c.1963_*1delTAAC		3_prime_UTR	Exon 17 of 17	NP_116250.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERAC1	ENST00000647468.2	MANE Select	c.1963_*1delTAAC	p.Ter655fs	frameshift stop_lost	Exon 17 of 17	ENSP00000496731.1	Q96JX3-1
	SERAC1	ENST00000647468.2	MANE Select	c.1963_*1delTAAC		3_prime_UTR	Exon 17 of 17	ENSP00000496731.1	Q96JX3-1
	SERAC1	ENST00000607742.5	TSL:1	n.*3241_*3244delTAAC		non_coding_transcript_exon	Exon 15 of 15	ENSP00000475523.1	U3KQG3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2

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

hg19: chr6-158532396;