rs6820411

Variant names:

• chr4-122924114-C-A
• rs6820411
• NM_145207.3:c.163+809C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_145207.3(AFG2A):​c.163+809C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 152,222 control chromosomes in the GnomAD database, including 817 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.

• Frequency: Genomes: 𝑓 0.089 (817 hom., cov: 32)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680
• Publications: 3 publications found

Genes affected

AFG2A (HGNC:18119): (AFG2 AAA ATPase homolog A) This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

AFG2A Gene-Disease associations (from GenCC):

• microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145207.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	NM_145207.3	MANE Select	c.163+809C>A		intron	N/A	NP_660208.2
	AFG2A	NM_001438322.1		c.163+809C>A		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.163+809C>A		intron	N/A	NP_001424842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.163+809C>A		intron	N/A	ENSP00000274008.3
	AFG2A	ENST00000422835.2	TSL:1	n.205+809C>A		intron	N/A
	AFG2A	ENST00000675612.1		c.163+809C>A		intron	N/A	ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.0896 AC: 13623 AN: 152104 Hom.: 816 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0850

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0895 AC: 13623 AN: 152222 Hom.: 817 Cov.: 32 AF XY: 0.0861 AC XY: 6408 AN XY: 74440

African (AFR) AF: 0.0251 AC: 1041 AN: 41550

American (AMR) AF: 0.0738 AC: 1129 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 509 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0848 AC: 409 AN: 4822

European-Finnish (FIN) AF: 0.0974 AC: 1032 AN: 10600

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9125 AN: 68002

Other (OTH) AF: 0.104 AC: 219 AN: 2112

Alfa AF: 0.106 Hom.: 130

Bravo AF: 0.0858

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		0.068
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs6820411; hg19: chr4-123845269;