6-108519667-A-G

Position:

• chr6-108519667-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145315.5(AFG1L):​c.1204-30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,148,788 control chromosomes in the GnomAD database, including 125,025 homozygotes. 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: 𝑓 0.52 (21828 hom., cov: 32)
  • Exomes 𝑓: 0.45 (103197 hom.)
• Consequence: AFG1L NM_145315.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AFG1L	NM_145315.5	c.1204-30A>G		intron_variant		ENST00000368977.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AFG1L	ENST00000368977.9	c.1204-30A>G		intron_variant		1	NM_145315.5	P1
	ENST00000659932.1	n.124-28214T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79023 AN: 151932 Hom.: 21802 Cov.: 32

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.506

GnomAD3 exomes AF: 0.442 AC: 102037 AN: 230620 Hom.: 23826 AF XY: 0.440 AC XY: 54732 AN XY: 124492

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.409

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.448 AC: 446450 AN: 996738 Hom.: 103197 Cov.: 13 AF XY: 0.446 AC XY: 228895 AN XY: 513482

Gnomad4 AFR exome AF: 0.725

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.458

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.520 AC: 79089 AN: 152050 Hom.: 21828 Cov.: 32 AF XY: 0.515 AC XY: 38256 AN XY: 74306

Gnomad4 AFR AF: 0.721

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.501

Alfa AF: 0.468 Hom.: 19811

Bravo AF: 0.527

Asia WGS AF: 0.348 AC: 1212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.022
DANN	Benign	0.34
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

Publications

LitVar

Other links and lift over

dbSNP: rs2274776; hg19: chr6-108840870; COSMIC: COSV64555074; COSMIC: COSV64555074;