20-6009794-T-A

Variant names:

• chr20-6009794-T-A
• rs1568615047
• NM_019095.6:c.326T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3_Moderate PP5

The NM_019095.6(CRLS1):​c.326T>A​(p.Ile109Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRLS1 NM_019095.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.05

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.

• PS1: Transcript NM_019095.6 (CRLS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 20-6009794-T-A is Pathogenic according to our data. Variant chr20-6009794-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2443703.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.326T>A	p.Ile109Asn	missense_variant	Exon 2 of 7	ENST00000378863.9	NP_061968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLS1	ENST00000378863.9	c.326T>A	p.Ile109Asn	missense_variant	Exon 2 of 7	1	NM_019095.6	ENSP00000368140.4
ENSG00000286235	ENST00000652720.1	c.2450T>A	p.Ile817Asn	missense_variant	Exon 19 of 24			ENSP00000498784.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251152 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.7	H;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.95
MutPred		0.78		Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);.;
MVP		0.71
MPC		0.73
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.90

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: rs1568615047; hg19: chr20-5990440;