chr4-122935717-T-C

Variant names:

• chr4-122935717-T-C
• rs780025409
• NM_145207.3:c.1151T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_145207.3(AFG2A):​c.1151T>C​(p.Ile384Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,424,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.04
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

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.1151T>C	p.Ile384Thr	missense	Exon 6 of 16	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.1151T>C	p.Ile384Thr	missense	Exon 6 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.1148T>C	p.Ile383Thr	missense	Exon 6 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.1151T>C	p.Ile384Thr	missense	Exon 6 of 16	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.1193T>C		non_coding_transcript_exon	Exon 6 of 15
	AFG2A	ENST00000675612.1		c.1148T>C	p.Ile383Thr	missense	Exon 6 of 17	ENSP00000502453.1	A0A6Q8PGU6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000436 AC: 1 AN: 229102 AF XY: 0.00000804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1424550 Hom.: 0 Cov.: 30 AF XY: 0.00000424 AC XY: 3 AN XY: 707520

African (AFR) AF: 0.00 AC: 0 AN: 31816

American (AMR) AF: 0.00 AC: 0 AN: 36990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24424

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 78130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1097228

Other (OTH) AF: 0.00 AC: 0 AN: 58694

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.83
MutPred		0.59		Gain of relative solvent accessibility (P = 0.005)
MVP		0.96
MPC		0.52
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.77
gMVP		0.80
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780025409; hg19: chr4-123856872;