Genetic Variant AFG1L:p.Cys23Tyr (chr6-108295147-G-A) – 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_145315.5(AFG1L):c.68G>A(p.Cys23Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AFG1L
NM_145315.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

Variant links:

Genes affected

AFG1L (HGNC:16411): (AFG1 like ATPase) This gene encodes a mitochondrial integral membrane protein that plays a role in mitochondrial protein homeostasis. The protein contains a P-loop motif and a five-domain structure that is conserved in fly, yeast, and bacteria. It functions to mediate the degradation of nuclear-encoded complex IV subunits. Two conserved estrogen receptor binding sites are located within 2.5 kb of this gene. Polymorphisms in this gene have been associated with bipolar disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2016]

AFG1L 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=0.12293777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG1L	NM_145315.5 link	c.68G>A	p.Cys23Tyr	missense_variant	Exon 1 of 13	ENST00000368977.9	NP_660358.2	Q8WV93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AFG1L	ENST00000368977.9 link	c.68G>A	p.Cys23Tyr	missense_variant	Exon 1 of 13	1	NM_145315.5	ENSP00000357973.3	Q8WV93
AFG1L	ENST00000430458.1 link	n.157G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5
AFG1L	ENST00000421954.5 link	c.-56G>A		upstream_gene_variant		5		ENSP00000398225.1	H0Y5F4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458224

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725544

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

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

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.68G>A (p.C23Y) alteration is located in exon 1 (coding exon 1) of the LACE1 gene. This alteration results from a G to A substitution at nucleotide position 68, causing the cysteine (C) at amino acid position 23 to be replaced by a tyrosine (Y). 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

0.099

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.066

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.74

M_CAP

Benign

0.0023

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.99

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.98

REVEL

Benign

0.080

Sift

Uncertain

0.022

Sift4G

Uncertain

0.0050

Polyphen

0.028

Vest4

0.39

MutPred

0.48

Gain of MoRF binding (P = 0.0706);

MVP

0.11

MPC

0.32

ClinPred

0.12

GERP RS

3.4

Varity_R

0.30

gMVP

0.40

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