NM_145207.3:c.80G>C

Variant names:

• chr4-122923222-G-C
• rs35430470
• NM_145207.3:c.80G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_145207.3(AFG2A):​c.80G>C​(p.Cys27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 1,614,156 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C27F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.043 (458 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (448 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.322
• Publications: 7 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.46019 (below the threshold of 3.09). Trascript score misZ: 1.2041 (below the threshold of 3.09). GenCC associations: The gene is linked to microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015427172).
• BP6: Variant 4-122923222-G-C is Benign according to our data. Variant chr4-122923222-G-C is described in ClinVar as Benign. ClinVar VariationId is 475736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 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.80G>C	p.Cys27Ser	missense	Exon 1 of 16	NP_660208.2
	AFG2A	NM_001438322.1		c.80G>C	p.Cys27Ser	missense	Exon 1 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.80G>C	p.Cys27Ser	missense	Exon 1 of 17	NP_001424842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2A	ENST00000274008.5	TSL:1 MANE Select	c.80G>C	p.Cys27Ser	missense	Exon 1 of 16	ENSP00000274008.3
	AFG2A	ENST00000422835.2	TSL:1	n.122G>C		non_coding_transcript_exon	Exon 1 of 15
	AFG2A	ENST00000675612.1		c.80G>C	p.Cys27Ser	missense	Exon 1 of 17	ENSP00000502453.1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6526 AN: 152162 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0119 AC: 2998 AN: 251454 AF XY: 0.00850

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00922

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00491 AC: 7174 AN: 1461874 Hom.: 448 Cov.: 31 AF XY: 0.00421 AC XY: 3063 AN XY: 727236

African (AFR) AF: 0.153 AC: 5110 AN: 33478

American (AMR) AF: 0.0103 AC: 461 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 389 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.000450 AC: 500 AN: 1112012

Other (OTH) AF: 0.0109 AC: 661 AN: 60394

GnomAD4 genome AF: 0.0429 AC: 6535 AN: 152282 Hom.: 458 Cov.: 32 AF XY: 0.0410 AC XY: 3051 AN XY: 74478

African (AFR) AF: 0.146 AC: 6081 AN: 41520

American (AMR) AF: 0.0173 AC: 264 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68026

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.00475 Hom.: 6

Bravo AF: 0.0479

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.141 AC: 620

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0138 AC: 1675

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.5
DANN	Benign	0.65
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.32
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.12
Sift	Benign	0.58	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.26		Gain of loop (P = 0.0166)
MPC		0.18
ClinPred		0.0037	T
GERP RS		2.3
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.12
Mutation Taster		=99/1	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: rs35430470; hg19: chr4-123844377;