4-123107627-C-T

Variant names:

• chr4-123107627-C-T
• rs307059
• NM_145207.3:c.2340+16922C>T

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+16922C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 152,098 control chromosomes in the GnomAD database, including 19,208 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 0.45 (19208 hom., cov: 33)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 1 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

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 = 0.605 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	NM_145207.3	MANE Select	c.2340+16922C>T		intron	N/A	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.2412+16922C>T		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.2409+16922C>T		intron	N/A	NP_001424842.1	A0A6Q8PGU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.2340+16922C>T		intron	N/A	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000675612.1		c.2409+16922C>T		intron	N/A	ENSP00000502453.1	A0A6Q8PGU6
	AFG2A	ENST00000905945.1		c.2337+16922C>T		intron	N/A	ENSP00000576004.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 69044 AN: 151980 Hom.: 19207 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.472

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

GnomAD4 genome AF: 0.454 AC: 69053 AN: 152098 Hom.: 19208 Cov.: 33 AF XY: 0.454 AC XY: 33733 AN XY: 74346

African (AFR) AF: 0.124 AC: 5159 AN: 41534

American (AMR) AF: 0.507 AC: 7754 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1745 AN: 3472

East Asian (EAS) AF: 0.511 AC: 2622 AN: 5128

South Asian (SAS) AF: 0.320 AC: 1544 AN: 4822

European-Finnish (FIN) AF: 0.661 AC: 6996 AN: 10590

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41437 AN: 67954

Other (OTH) AF: 0.473 AC: 1000 AN: 2112

Alfa AF: 0.533 Hom.: 3016

Bravo AF: 0.433

Asia WGS AF: 0.441 AC: 1531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.16
PhyloP100		0.30
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs307059;

hg19: chr4-124028782;