chr4-123097249-A-G

Variant names:

• chr4-123097249-A-G
• rs10518410
• NM_145207.3:c.2340+6544A>G

Variant summary

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

The NM_145207.3(AFG2A):​c.2340+6544A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,108 control chromosomes in the GnomAD database, including 933 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 0.10 (933 hom., cov: 32)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.258
• 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 -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 = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3	c.2340+6544A>G		intron_variant	Intron 14 of 15	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG2A	ENST00000274008.5	c.2340+6544A>G		intron_variant	Intron 14 of 15	1	NM_145207.3	ENSP00000274008.3
AFG2A	ENST00000422835.2	n.2383-4935A>G		intron_variant	Intron 14 of 14	1
AFG2A	ENST00000675612.1	c.2409+6544A>G		intron_variant	Intron 15 of 16			ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15894 AN: 151990 Hom.: 928 Cov.: 32

Gnomad AFR AF: 0.0851

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0791

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.105 AC: 15916 AN: 152108 Hom.: 933 Cov.: 32 AF XY: 0.0993 AC XY: 7387 AN XY: 74390

African (AFR) AF: 0.0855 AC: 3548 AN: 41514

American (AMR) AF: 0.0790 AC: 1204 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 530 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0828 AC: 400 AN: 4828

European-Finnish (FIN) AF: 0.0743 AC: 788 AN: 10608

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9040 AN: 67944

Other (OTH) AF: 0.117 AC: 246 AN: 2110

Alfa AF: 0.129 Hom.: 2138

Bravo AF: 0.105

Asia WGS AF: 0.0420 AC: 145 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	1.3
DANN	Benign	0.37
PhyloP100		-0.26
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: rs10518410; hg19: chr4-124018404;