4-122934487-G-T

Variant names:

• chr4-122934487-G-T
• rs75871497
• NM_145207.3:c.896G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_145207.3(AFG2A):​c.896G>T​(p.Gly299Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.0600
• 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 -8 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=0.003907591).
• BP6: Variant 4-122934487-G-T is Benign according to our data. Variant chr4-122934487-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475737.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (247/152330) while in subpopulation AFR AF = 0.00556 (231/41570). AF 95% confidence interval is 0.00497. There are 0 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.896G>T	p.Gly299Val	missense	Exon 5 of 16	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.896G>T	p.Gly299Val	missense	Exon 5 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.893G>T	p.Gly298Val	missense	Exon 5 of 17	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.896G>T	p.Gly299Val	missense	Exon 5 of 16	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.938G>T		non_coding_transcript_exon	Exon 5 of 15
	AFG2A	ENST00000675612.1		c.893G>T	p.Gly298Val	missense	Exon 5 of 17	ENSP00000502453.1	A0A6Q8PGU6

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000334 AC: 84 AN: 251258 AF XY: 0.000250

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727242

African (AFR) AF: 0.00466 AC: 156 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.000331 AC: 20 AN: 60396

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74490

African (AFR) AF: 0.00556 AC: 231 AN: 41570

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000632 Hom.: 1

Bravo AF: 0.00177

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (2)
-	-	1	AFG2A-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0039	T
MetaSVM	Uncertain	-0.19	T
PhyloP100		-0.060
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Benign	0.21	T
Sift4G	Benign	0.38	T
Polyphen		0.0020	B
Vest4		0.15
MVP		0.52
MPC		0.18
ClinPred		0.0025	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.43
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75871497; hg19: chr4-123855642;