chr6-108519667-A-C

Variant names:

• chr6-108519667-A-C
• rs2274776
• NM_145315.5:c.1204-30A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145315.5(AFG1L):​c.1204-30A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000002 in 999,574 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: AFG1L NM_145315.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• 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]

ENSG00000287044 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG1L	NM_145315.5	c.1204-30A>C		intron_variant	Intron 11 of 12	ENST00000368977.9	NP_660358.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG1L	ENST00000368977.9	c.1204-30A>C		intron_variant	Intron 11 of 12	1	NM_145315.5	ENSP00000357973.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000200 AC: 2 AN: 999574 Hom.: 0 Cov.: 13 AF XY: 0.00000388 AC XY: 2 AN XY: 514934

African (AFR) AF: 0.00 AC: 0 AN: 23836

American (AMR) AF: 0.00 AC: 0 AN: 37694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22276

East Asian (EAS) AF: 0.00 AC: 0 AN: 37374

South Asian (SAS) AF: 0.0000276 AC: 2 AN: 72334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4792

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 703734

Other (OTH) AF: 0.00 AC: 0 AN: 45150

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.021
DANN	Benign	0.44
PhyloP100		-1.2
BranchPoint Hunter		1.0

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: rs2274776; hg19: chr6-108840870;