6-108295165-G-T

Position:

• chr6-108295165-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145315.5(AFG1L):​c.86G>T​(p.Trp29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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: 0.0000034 (0 hom.)
• Consequence: AFG1L NM_145315.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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]

ACMG classification

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=0.12915283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFG1L	NM_145315.5	c.86G>T	p.Trp29Leu	missense_variant	1/13	ENST00000368977.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG1L	ENST00000368977.9	c.86G>T	p.Trp29Leu	missense_variant	1/13	1	NM_145315.5	P1
AFG1L	ENST00000430458.1	n.175G>T		non_coding_transcript_exon_variant	1/4	5
AFG1L	ENST00000421954.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456712 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724842

Gnomad4 AFR exome AF: 0.000149

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.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.86G>T (p.W29L) alteration is located in exon 1 (coding exon 1) of the LACE1 gene. This alteration results from a G to T substitution at nucleotide position 86, causing the tryptophan (W) at amino acid position 29 to be replaced by a leucine (L). 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	0.088
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.17
Sift	Benign	0.23	T
Sift4G	Benign	0.65	T
Polyphen		0.016	B
Vest4		0.33
MutPred		0.53		Loss of catalytic residue at W29 (P = 0.029);
MVP		0.29
MPC		0.30
ClinPred		0.27	T
GERP RS		2.7
Varity_R		0.18
gMVP		0.33

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: rs1364234065; hg19: chr6-108616369;