NM_145315.5:c.119C>G

Variant names:

• chr6-108295198-C-G
• rs760008630
• NM_145315.5:c.119C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145315.5(AFG1L):​c.119C>G​(p.Pro40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 6.9e-7 (0 hom.)
• Consequence: AFG1L NM_145315.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.586
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13858727).

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.119C>G	p.Pro40Arg	missense	Exon 1 of 13	NP_660358.2
	AFG1L	NM_001323005.2		c.119C>G	p.Pro40Arg	missense	Exon 1 of 12	NP_001309934.1
	AFG1L	NR_136553.2		n.145C>G		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG1L	ENST00000368977.9	TSL:1 MANE Select	c.119C>G	p.Pro40Arg	missense	Exon 1 of 13	ENSP00000357973.3	Q8WV93
	AFG1L	ENST00000908138.1		c.119C>G	p.Pro40Arg	missense	Exon 1 of 14	ENSP00000578197.1
	AFG1L	ENST00000908137.1		c.119C>G	p.Pro40Arg	missense	Exon 1 of 13	ENSP00000578196.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000413 AC: 1 AN: 242348 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723082

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111796

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

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	0.070
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.59
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.026
Sift	Uncertain	0.016	D
Sift4G	Benign	0.074	T
Polyphen		0.38	B
Vest4		0.25
MutPred		0.37		Loss of loop (P = 0.0075)
MVP		0.38
MPC		0.18
ClinPred		0.48	T
GERP RS		4.5
PromoterAI		0.078	Neutral
Varity_R		0.13
gMVP		0.35
Mutation Taster		=72/28	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: rs760008630; hg19: chr6-108616402;