chr6-108356698-C-A

Variant names:

• chr6-108356698-C-A
• rs1337014099
• NM_145315.5:c.526C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145315.5(AFG1L):​c.526C>A​(p.Arg176Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,449,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.0000021 (0 hom.)
• Consequence: AFG1L NM_145315.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.52

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28395182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG1L	NM_145315.5	c.526C>A	p.Arg176Ser	missense_variant	Exon 5 of 13	ENST00000368977.9	NP_660358.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG1L	ENST00000368977.9	c.526C>A	p.Arg176Ser	missense_variant	Exon 5 of 13	1	NM_145315.5	ENSP00000357973.3
AFG1L	ENST00000421954.5	c.127C>A	p.Arg43Ser	missense_variant	Exon 3 of 11	5		ENSP00000398225.1
AFG1L	ENST00000437715.1	c.427C>A	p.Arg143Ser	missense_variant	Exon 6 of 6	5		ENSP00000392085.1
AFG1L	ENST00000431865.1	n.7C>A		non_coding_transcript_exon_variant	Exon 1 of 8	5		ENSP00000415484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449114 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 720546

Gnomad4 AFR exome AF: 0.0000606

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.0041	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T;.
Eigen	Benign	0.029
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.11
Sift	Benign	0.15	T;T
Sift4G	Benign	0.41	T;D
Polyphen		0.048	B;.
Vest4		0.59
MutPred		0.45		Gain of phosphorylation at R176 (P = 0.0261);.;
MVP		0.21
MPC		0.38
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.35
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1337014099; hg19: chr6-108677902;