NM_024063.3:c.-25C>T

Variant names:

• chr15-45402405-C-T
• rs79861633
• NM_024063.3:c.-25C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024063.3(AFG2B):​c.-25C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,573,130 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (103 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (82 hom.)
• Consequence: AFG2B NM_024063.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.239
• Publications: 0 publications found

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]

GATM Gene-Disease associations (from GenCC):

• AGAT deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Fanconi renotubular syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 15-45402405-C-T is Benign according to our data. Variant chr15-45402405-C-T is described in ClinVar as Benign. ClinVar VariationId is 1265267.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024063.3. 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
	AFG2B	NM_024063.3	MANE Select	c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_076968.2	Q9BVQ7-1
	AFG2B	NM_024063.3	MANE Select	c.-25C>T		5_prime_UTR	Exon 1 of 8	NP_076968.2	Q9BVQ7-1
	AFG2B	NM_001323640.2		c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001310569.1	Q9BVQ7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG2B	ENST00000305560.11	TSL:1 MANE Select	c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000305494.6	Q9BVQ7-1
	AFG2B	ENST00000305560.11	TSL:1 MANE Select	c.-25C>T		5_prime_UTR	Exon 1 of 8	ENSP00000305494.6	Q9BVQ7-1
	AFG2B	ENST00000907461.1		c.-25C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000577520.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2859 AN: 152200 Hom.: 102 Cov.: 34

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00418 AC: 890 AN: 212752 AF XY: 0.00286

Gnomad AFR exome AF: 0.0659

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000392

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00161 AC: 2285 AN: 1420812 Hom.: 82 Cov.: 33 AF XY: 0.00129 AC XY: 914 AN XY: 706044

African (AFR) AF: 0.0673 AC: 1981 AN: 29424

American (AMR) AF: 0.00178 AC: 61 AN: 34258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24320

East Asian (EAS) AF: 0.00 AC: 0 AN: 36724

South Asian (SAS) AF: 0.000124 AC: 10 AN: 80818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5672

European-Non Finnish (NFE) AF: 0.0000155 AC: 17 AN: 1097828

Other (OTH) AF: 0.00365 AC: 214 AN: 58616

GnomAD4 genome AF: 0.0188 AC: 2868 AN: 152318 Hom.: 103 Cov.: 34 AF XY: 0.0181 AC XY: 1349 AN XY: 74482

African (AFR) AF: 0.0664 AC: 2761 AN: 41582

American (AMR) AF: 0.00542 AC: 83 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.0111 Hom.: 16

Bravo AF: 0.0213

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.7
DANN	Benign	0.76
PhyloP100		-0.24
PromoterAI		-0.080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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: rs79861633; hg19: chr15-45694603;