15-45402524-G-A

Variant names:

• chr15-45402524-G-A
• NM_024063.3:c.95G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024063.3(AFG2B):​c.95G>A​(p.Gly32Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,449,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: AFG2B NM_024063.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.02

Genes affected

AFG2B (HGNC:28762): (AFG2 AAA ATPase homolog B) Predicted to enable ATP binding activity. Located in cytoplasm and spindle. [provided by Alliance of Genome Resources, Apr 2022]

GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2B	NM_024063.3	c.95G>A	p.Gly32Asp	missense_variant	Exon 1 of 8	ENST00000305560.11	NP_076968.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA5L1	ENST00000305560.11	c.95G>A	p.Gly32Asp	missense_variant	Exon 1 of 8	1	NM_024063.3	ENSP00000305494.6
SPATA5L1	ENST00000531970.5	n.95G>A		non_coding_transcript_exon_variant	Exon 1 of 8	2		ENSP00000436823.1
SPATA5L1	ENST00000559860.2	n.155G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2
GATM	ENST00000458245.5	n.-197C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000255 AC: 37 AN: 1449026 Hom.: 0 Cov.: 33 AF XY: 0.0000222 AC XY: 16 AN XY: 720154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Neurodevelopmental disorder with hearing loss and spasticity Uncertain:1

Dec 21, 2022

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0039	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.53	N;.
REVEL	Uncertain	0.62
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.37		Loss of MoRF binding (P = 0.0828);Loss of MoRF binding (P = 0.0828);
MVP		0.83
MPC		2.4
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.27
gMVP		0.91

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-45694722;