4-123096501-G-C

Variant names:

• chr4-123096501-G-C
• rs307022
• NM_145207.3:c.2340+5796G>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.2340+5796G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 151,858 control chromosomes in the GnomAD database, including 41,052 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 0.73 (41052 hom., cov: 31)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.167
• Publications: 3 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=-0.49).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 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+5796G>C		intron	N/A	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.2412+5796G>C		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.2409+5796G>C		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+5796G>C		intron	N/A	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.2383-5683G>C		intron	N/A
	AFG2A	ENST00000675612.1		c.2409+5796G>C		intron	N/A	ENSP00000502453.1	A0A6Q8PGU6

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110838 AN: 151740 Hom.: 41028 Cov.: 31

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.805

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.707

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

GnomAD4 genome AF: 0.730 AC: 110905 AN: 151858 Hom.: 41052 Cov.: 31 AF XY: 0.738 AC XY: 54752 AN XY: 74234

African (AFR) AF: 0.612 AC: 25340 AN: 41376

American (AMR) AF: 0.734 AC: 11178 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2475 AN: 3466

East Asian (EAS) AF: 0.972 AC: 5035 AN: 5182

South Asian (SAS) AF: 0.805 AC: 3865 AN: 4804

European-Finnish (FIN) AF: 0.830 AC: 8791 AN: 10586

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51756 AN: 67908

Other (OTH) AF: 0.711 AC: 1498 AN: 2106

Alfa AF: 0.745 Hom.: 4998

Bravo AF: 0.716

Asia WGS AF: 0.867 AC: 3014 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.1
DANN	Benign	0.36
PhyloP100		0.17
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: rs307022; hg19: chr4-124017656;