chr15-45361394-A-G

Variant names:

• chr15-45361394-A-G
• rs1049508
• NM_001482.3:c.*715T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001482.3(GATM):​c.*715T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,928 control chromosomes in the GnomAD database, including 20,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (20335 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.355
• Publications: 19 publications found

Genes affected

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-45361394-A-G is Benign according to our data. Variant chr15-45361394-A-G is described in ClinVar as Benign. ClinVar VariationId is 316204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001482.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	NM_001482.3	MANE Select	c.*715T>C		3_prime_UTR	Exon 9 of 9	NP_001473.1
	GATM	NM_001321015.2		c.*715T>C		3_prime_UTR	Exon 12 of 12	NP_001307944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	ENST00000396659.8	TSL:1 MANE Select	c.*715T>C		3_prime_UTR	Exon 9 of 9	ENSP00000379895.3
	GATM	ENST00000558362.5	TSL:1	n.3643T>C		non_coding_transcript_exon	Exon 8 of 8
	GATM	ENST00000887717.1		c.*715T>C		3_prime_UTR	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69797 AN: 151804 Hom.: 20275 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.835

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.438

GnomAD4 exome AF: 0.167 AC: 1 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.460 AC: 69915 AN: 151922 Hom.: 20335 Cov.: 32 AF XY: 0.464 AC XY: 34450 AN XY: 74258

African (AFR) AF: 0.783 AC: 32407 AN: 41414

American (AMR) AF: 0.515 AC: 7856 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1208 AN: 3470

East Asian (EAS) AF: 0.835 AC: 4316 AN: 5166

South Asian (SAS) AF: 0.407 AC: 1957 AN: 4810

European-Finnish (FIN) AF: 0.307 AC: 3250 AN: 10570

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.261 AC: 17731 AN: 67938

Other (OTH) AF: 0.445 AC: 939 AN: 2112

Alfa AF: 0.332 Hom.: 7687

Bravo AF: 0.496

Asia WGS AF: 0.629 AC: 2165 AN: 3450

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arginine:glycine amidinotransferase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.1
DANN	Benign	0.84
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs1049508; hg19: chr15-45653592;