Genetic Variant CRLS1:p.Ala17Ser (chr20-6006295-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019095.6(CRLS1):c.49G>T(p.Ala17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRLS1
NM_019095.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Variant links:

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 links:

ENSG00000286235 (HGNC:):

ENSG00000286235 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08859378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLS1	NM_019095.6 link	c.49G>T	p.Ala17Ser	missense_variant	Exon 1 of 7	ENST00000378863.9	NP_061968.1	Q9UJA2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRLS1	ENST00000378863.9 link	c.49G>T	p.Ala17Ser	missense_variant	Exon 1 of 7	1	NM_019095.6	ENSP00000368140.4	Q9UJA2-1
CRLS1	ENST00000452938.5 link	c.49G>T	p.Ala17Ser	missense_variant	Exon 1 of 6	1		ENSP00000416770.1	Q6NTG3
ENSG00000286235	ENST00000652720.1 link	c.2431-3480G>T		intron_variant	Intron 18 of 23			ENSP00000498784.1	A0A494C100

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1146244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

553748

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49G>T (p.A17S) alteration is located in exon 1 (coding exon 1) of the CRLS1 gene. This alteration results from a G to T substitution at nucleotide position 49, causing the alanine (A) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.49

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.080

N;N

REVEL

Benign

0.022

Sift

Benign

0.15

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.28

B;.

Vest4

0.19

MutPred

0.26

Gain of glycosylation at A17 (P = 0.0218);Gain of glycosylation at A17 (P = 0.0218);

MVP

0.081

MPC

0.13

ClinPred

0.15

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Varity_R

0.088

gMVP

0.36

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over