chr4-123146653-C-T

Variant names:

• chr4-123146653-C-T
• rs303083
• NM_145207.3:c.2340+55948C>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+55948C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 152,092 control chromosomes in the GnomAD database, including 33,089 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 0.61 (33089 hom., cov: 32)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 2 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, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 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+55948C>T		intron	N/A	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.2412+55948C>T		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.2409+55948C>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+55948C>T		intron	N/A	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000675612.1		c.2409+55948C>T		intron	N/A	ENSP00000502453.1	A0A6Q8PGU6
	AFG2A	ENST00000905945.1		c.2337+55948C>T		intron	N/A	ENSP00000576004.1

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92652 AN: 151974 Hom.: 33077 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.609 AC: 92675 AN: 152092 Hom.: 33089 Cov.: 32 AF XY: 0.618 AC XY: 45979 AN XY: 74356

African (AFR) AF: 0.214 AC: 8883 AN: 41472

American (AMR) AF: 0.685 AC: 10457 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2311 AN: 3468

East Asian (EAS) AF: 0.965 AC: 5001 AN: 5180

South Asian (SAS) AF: 0.716 AC: 3452 AN: 4822

European-Finnish (FIN) AF: 0.831 AC: 8798 AN: 10590

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51514 AN: 67966

Other (OTH) AF: 0.620 AC: 1310 AN: 2112

Alfa AF: 0.576 Hom.: 2555

Bravo AF: 0.579

Asia WGS AF: 0.789 AC: 2743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.7
DANN	Benign	0.58
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: rs303083; hg19: chr4-124067808;