4-122947078-A-G

Variant names:

• chr4-122947078-A-G
• rs6534368
• NM_145207.3:c.1459-155A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145207.3(AFG2A):​c.1459-155A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 152,280 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.053 (524 hom., cov: 33)
• Consequence: AFG2A NM_145207.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.80
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-122947078-A-G is Benign according to our data. Variant chr4-122947078-A-G is described in ClinVar as Benign. ClinVar VariationId is 448459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	NM_145207.3	MANE Select	c.1459-155A>G		intron	N/A	NP_660208.2
	AFG2A	NM_001438322.1		c.1459-155A>G		intron	N/A	NP_001425251.1
	AFG2A	NM_001437913.1		c.1456-155A>G		intron	N/A	NP_001424842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.1459-155A>G		intron	N/A	ENSP00000274008.3
	AFG2A	ENST00000422835.2	TSL:1	n.1501-155A>G		intron	N/A
	AFG2A	ENST00000675612.1		c.1456-155A>G		intron	N/A	ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8128 AN: 152162 Hom.: 522 Cov.: 33

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0450

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

GnomAD4 genome AF: 0.0535 AC: 8144 AN: 152280 Hom.: 524 Cov.: 33 AF XY: 0.0522 AC XY: 3887 AN XY: 74462

African (AFR) AF: 0.156 AC: 6483 AN: 41538

American (AMR) AF: 0.0285 AC: 436 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1008 AN: 68030

Other (OTH) AF: 0.0445 AC: 94 AN: 2112

Alfa AF: 0.0233 Hom.: 29

Bravo AF: 0.0612

Asia WGS AF: 0.0110 AC: 38 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		1.8
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: rs6534368; hg19: chr4-123868233;