rs6534369

Variant names:

• chr4-122947301-C-T
• rs6534369
• NM_145207.3:c.1527C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_145207.3(AFG2A):​c.1527C>T​(p.Leu509Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,388 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (522 hom., cov: 32)
  • Exomes 𝑓: 0.018 (739 hom.)
• Consequence: AFG2A NM_145207.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0470
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-122947301-C-T is Benign according to our data. Variant chr4-122947301-C-T is described in ClinVar as Benign. ClinVar VariationId is 448460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.047 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3	c.1527C>T	p.Leu509Leu	synonymous_variant	Exon 9 of 16	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG2A	ENST00000274008.5	c.1527C>T	p.Leu509Leu	synonymous_variant	Exon 9 of 16	1	NM_145207.3	ENSP00000274008.3
AFG2A	ENST00000422835.2	n.1569C>T		non_coding_transcript_exon_variant	Exon 9 of 15	1
AFG2A	ENST00000675612.1	c.1524C>T	p.Leu508Leu	synonymous_variant	Exon 9 of 17			ENSP00000502453.1
AFG2A	ENST00000674886.1	n.1589C>T		non_coding_transcript_exon_variant	Exon 9 of 11

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8111 AN: 152008 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0454

GnomAD2 exomes AF: 0.0210 AC: 5259 AN: 251000 AF XY: 0.0182

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0180 AC: 26365 AN: 1461264 Hom.: 739 Cov.: 31 AF XY: 0.0168 AC XY: 12223 AN XY: 726934

African (AFR) AF: 0.164 AC: 5502 AN: 33454

American (AMR) AF: 0.0162 AC: 725 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 656 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00132 AC: 114 AN: 86204

European-Finnish (FIN) AF: 0.00487 AC: 260 AN: 53396

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5766

European-Non Finnish (NFE) AF: 0.0158 AC: 17610 AN: 1111584

Other (OTH) AF: 0.0234 AC: 1413 AN: 60372

GnomAD4 genome AF: 0.0534 AC: 8127 AN: 152124 Hom.: 522 Cov.: 32 AF XY: 0.0522 AC XY: 3879 AN XY: 74376

African (AFR) AF: 0.156 AC: 6471 AN: 41434

American (AMR) AF: 0.0283 AC: 432 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1007 AN: 68014

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0292 Hom.: 697

Bravo AF: 0.0612

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	5.8
DANN	Benign	0.73
PhyloP100		0.047
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=98/2	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: rs6534369; hg19: chr4-123868456;