chr6-108323896-G-A

Variant names:

• chr6-108323896-G-A
• rs186208029
• NM_145315.5:c.211G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_145315.5(AFG1L):​c.211G>A​(p.Val71Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,614,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: AFG1L NM_145315.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 6 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024918526).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145315.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG1L	NM_145315.5	MANE Select	c.211G>A	p.Val71Ile	missense	Exon 2 of 13	NP_660358.2
	AFG1L	NM_001323005.2		c.211G>A	p.Val71Ile	missense	Exon 2 of 12	NP_001309934.1
	AFG1L	NR_136553.2		n.165+28678G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG1L	ENST00000368977.9	TSL:1 MANE Select	c.211G>A	p.Val71Ile	missense	Exon 2 of 13	ENSP00000357973.3	Q8WV93
	AFG1L	ENST00000908138.1		c.262G>A	p.Val88Ile	missense	Exon 3 of 14	ENSP00000578197.1
	AFG1L	ENST00000908137.1		c.211G>A	p.Val71Ile	missense	Exon 2 of 13	ENSP00000578196.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251466 AF XY: 0.000302

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000979

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00131 AC: 52 AN: 39698

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111996

Other (OTH) AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74462

African (AFR) AF: 0.0000722 AC: 3 AN: 41534

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4808

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.048
Sift	Benign	0.25	T
Sift4G	Benign	0.40	T
Polyphen		0.0020	B
Vest4		0.083
MVP		0.24
MPC		0.14
ClinPred		0.013	T
GERP RS		1.3
Varity_R		0.030
gMVP		0.19
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs186208029; hg19: chr6-108645100; COSMIC: COSV64559214;