20-6009794-TC-AT

Variant names:

• chr20-6009794-TC-AT
• NM_019095.6:c.326_327delTCinsAT
• CRLS1 p.Ile109Asn

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_019095.6(CRLS1):​c.326_327delTCinsAT​(p.Ile109Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRLS1 NM_019095.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

Genes affected

CRLS1 (HGNC:16148): (cardiolipin synthase 1) This gene encodes a member of the CDP-alcohol phosphatidyltransferase class-I family of proteins. The encoded enzyme catalyzes the synthesis of cardiolipin, a phospholipid component of mitochondrial membranes that is critical for mitochondrial function. [provided by RefSeq, Apr 2016]

CRLS1 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 57

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000286235 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_019095.6 (CRLS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019095.6. 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
	CRLS1	NM_019095.6	MANE Select	c.326_327delTCinsAT	p.Ile109Asn	missense	N/A	NP_061968.1	Q9UJA2-1
	CRLS1	NM_001127458.2		c.29_30delTCinsAT	p.Ile10Asn	missense	N/A	NP_001120930.1	Q9UJA2-2
	CRLS1	NM_001323561.2		c.-8_-7delTCinsAT		5_prime_UTR	Exon 2 of 7	NP_001310490.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLS1	ENST00000378863.9	TSL:1 MANE Select	c.326_327delTCinsAT	p.Ile109Asn	missense	N/A	ENSP00000368140.4	Q9UJA2-1
	ENSG00000286235	ENST00000652720.1		c.2450_2451delTCinsAT	p.Ile817Asn	missense	N/A	ENSP00000498784.1	A0A494C100
	CRLS1	ENST00000452938.5	TSL:1	c.326_327delTCinsAT	p.Ile109Asn	missense	N/A	ENSP00000416770.1	Q6NTG3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-5990440;