rs1337014099

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-108356698-C-A
• chr6-108356698-C-G
• chr6-108356698-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176C) has been classified as Uncertain significance.

• 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
• Publications: 1 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 1 ACMG points.

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

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.526C>A	p.Arg176Ser	missense	Exon 5 of 13	NP_660358.2
	AFG1L	NM_001323005.2		c.526C>A	p.Arg176Ser	missense	Exon 5 of 12	NP_001309934.1
	AFG1L	NR_136553.2		n.174C>A		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG1L	ENST00000368977.9	TSL:1 MANE Select	c.526C>A	p.Arg176Ser	missense	Exon 5 of 13	ENSP00000357973.3	Q8WV93
	AFG1L	ENST00000908138.1		c.577C>A	p.Arg193Ser	missense	Exon 6 of 14	ENSP00000578197.1
	AFG1L	ENST00000908137.1		c.520C>A	p.Arg174Ser	missense	Exon 5 of 13	ENSP00000578196.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000606 AC: 2 AN: 33018

American (AMR) AF: 0.00 AC: 0 AN: 43038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 83250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105680

Other (OTH) AF: 0.00 AC: 0 AN: 59920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000625500), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.95	T
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Benign	0.41	T
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
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs1337014099; hg19: chr6-108677902;