NM_145315.5:c.1204-30A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• 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).
• 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 rank	MANE	Protein	UniProt
AFG1L	NM_145315.5	c.1204-30A>G		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>G		intron_variant	Intron 11 of 12	1	NM_145315.5	ENSP00000357973.3

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

GnomAD2 exomes AF: 0.442 AC: 102037 AN: 230620 AF XY: 0.440

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 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

African (AFR) AF: 0.725 AC: 17260 AN: 23794

American (AMR) AF: 0.357 AC: 13418 AN: 37614

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 9022 AN: 22226

East Asian (EAS) AF: 0.257 AC: 9577 AN: 37334

South Asian (SAS) AF: 0.406 AC: 29288 AN: 72212

European-Finnish (FIN) AF: 0.456 AC: 23857 AN: 52272

Middle Eastern (MID) AF: 0.463 AC: 2213 AN: 4782

European-Non Finnish (NFE) AF: 0.458 AC: 321584 AN: 701438

Other (OTH) AF: 0.449 AC: 20231 AN: 45066

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

African (AFR) AF: 0.721 AC: 29889 AN: 41456

American (AMR) AF: 0.430 AC: 6579 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1387 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1430 AN: 5166

South Asian (SAS) AF: 0.420 AC: 2024 AN: 4822

European-Finnish (FIN) AF: 0.461 AC: 4862 AN: 10552

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31235 AN: 67982

Other (OTH) AF: 0.501 AC: 1059 AN: 2114

Alfa AF: 0.477 Hom.: 26203

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
PhyloP100		-1.2
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV64555074; COSMIC: COSV64555074;