chr4-122934637-A-T

Variant names:

• chr4-122934637-A-T
• rs146372781
• NM_145207.3:c.1046A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_145207.3(AFG2A):​c.1046A>T​(p.Lys349Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K349R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AFG2A NM_145207.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.545
• 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: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26706782).

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.1046A>T	p.Lys349Ile	missense	Exon 5 of 16	NP_660208.2	Q8NB90-1
	AFG2A	NM_001438322.1		c.1046A>T	p.Lys349Ile	missense	Exon 5 of 17	NP_001425251.1
	AFG2A	NM_001437913.1		c.1043A>T	p.Lys348Ile	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.1046A>T	p.Lys349Ile	missense	Exon 5 of 16	ENSP00000274008.3	Q8NB90-1
	AFG2A	ENST00000422835.2	TSL:1	n.1088A>T		non_coding_transcript_exon	Exon 5 of 15
	AFG2A	ENST00000675612.1		c.1043A>T	p.Lys348Ile	missense	Exon 5 of 17	ENSP00000502453.1	A0A6Q8PGU6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461526 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727034

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.28	D
PhyloP100		0.55
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.034	D
Polyphen		0.29	B
Vest4		0.39
MutPred		0.46		Loss of methylation at K349 (P = 6e-04)
MVP		0.86
MPC		0.27
ClinPred		0.98	D
GERP RS		-3.4
Varity_R		0.23
gMVP		0.70
Mutation Taster		=87/13	polymorphism

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: rs146372781; hg19: chr4-123855792;