20-6015431-C-A

Variant names:

• chr20-6015431-C-A
• rs759395960
• NM_019095.6:c.515C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_019095.6(CRLS1):​c.515C>A​(p.Ala172Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRLS1 NM_019095.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.71

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]

ENSG00000286235 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 20-6015431-C-A is Pathogenic according to our data. Variant chr20-6015431-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2443704.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLS1	NM_019095.6	c.515C>A	p.Ala172Asp	missense_variant	Exon 3 of 7	ENST00000378863.9	NP_061968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLS1	ENST00000378863.9	c.515C>A	p.Ala172Asp	missense_variant	Exon 3 of 7	1	NM_019095.6	ENSP00000368140.4
ENSG00000286235	ENST00000652720.1	c.2639C>A	p.Ala880Asp	missense_variant	Exon 20 of 24			ENSP00000498784.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459822 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined oxidative phosphorylation deficiency 57 Pathogenic:1

Jan 06, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.6	H;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.97
MutPred		0.87		Gain of disorder (P = 0.0921);Gain of disorder (P = 0.0921);.;
MVP		0.92
MPC		0.58
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.82
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs759395960; hg19: chr20-5996077;