4-123264524-T-C

Variant names:

• chr4-123264524-T-C
• rs11735364
• NM_145207.3:c.2505+8344T>C

Variant summary

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

The NM_145207.3(AFG2A):​c.2505+8344T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,044 control chromosomes in the GnomAD database, including 39,221 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 0.70 (39221 hom., cov: 32)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.268
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3	c.2505+8344T>C		intron_variant	Intron 15 of 15	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG2A	ENST00000274008.5	c.2505+8344T>C		intron_variant	Intron 15 of 15	1	NM_145207.3	ENSP00000274008.3
AFG2A	ENST00000675612.1	c.2574+8344T>C		intron_variant	Intron 16 of 16			ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106636 AN: 151926 Hom.: 39216 Cov.: 32

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.894

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.726

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

GnomAD4 genome AF: 0.702 AC: 106685 AN: 152044 Hom.: 39221 Cov.: 32 AF XY: 0.700 AC XY: 52075 AN XY: 74360

African (AFR) AF: 0.475 AC: 19652 AN: 41416

American (AMR) AF: 0.764 AC: 11676 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2471 AN: 3470

East Asian (EAS) AF: 0.559 AC: 2895 AN: 5176

South Asian (SAS) AF: 0.581 AC: 2794 AN: 4812

European-Finnish (FIN) AF: 0.894 AC: 9483 AN: 10602

Middle Eastern (MID) AF: 0.688 AC: 201 AN: 292

European-Non Finnish (NFE) AF: 0.812 AC: 55180 AN: 67972

Other (OTH) AF: 0.726 AC: 1534 AN: 2114

Alfa AF: 0.775 Hom.: 76217

Bravo AF: 0.687

Asia WGS AF: 0.636 AC: 2210 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		0.27
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: rs11735364; hg19: chr4-124185679;