rs192416474

Variant names:

• chr19-1399202-G-A
• rs192416474
• NM_000156.6:c.392-7C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1399202-G-A
• chr19-1399202-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.392-7C>T variant in GAMT is a nucleotide substitution in intron 3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00430 (107/24892 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 4 homozygotes in gnomAD v2.1.1 (all in the S Asian population) which, given the early onset and severity of phenotype for GAMT deficiency, supporting that the variant is not associated with GAMT deficiency. Computational evidence from SpliceAI and varSEAK suggests no impact on the gene/gene product (BP4). There is a ClinVar entry for this variant (Variation ID: 137436,). In summary, this variant meets the criteria to be classified as Benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA291019/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (8 hom.)
• Consequence: GAMT NM_000156.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003445
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -1.99
• Publications: 0 publications found

Genes affected

GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

GAMT Gene-Disease associations (from GenCC):

• guanidinoacetate methyltransferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. 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
	GAMT	NM_000156.6	MANE Select	c.392-7C>T		splice_region intron	N/A	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.392-7C>T		splice_region intron	N/A	NP_620279.1	Q14353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.392-7C>T		splice_region intron	N/A	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.662-7C>T		splice_region intron	N/A	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.392-7C>T		splice_region intron	N/A	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000662 AC: 166 AN: 250786 AF XY: 0.000736

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000383 AC: 559 AN: 1461118 Hom.: 8 Cov.: 34 AF XY: 0.000453 AC XY: 329 AN XY: 726880

African (AFR) AF: 0.00493 AC: 165 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00276 AC: 238 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52718

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000944 AC: 105 AN: 1111970

Other (OTH) AF: 0.000596 AC: 36 AN: 60382

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74468

African (AFR) AF: 0.00455 AC: 189 AN: 41546

American (AMR) AF: 0.000523 AC: 8 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000961 Hom.: 0

Bravo AF: 0.00128

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of guanidinoacetate methyltransferase (3)
-	-	3	not specified (3)
-	-	1	Cerebral creatine deficiency syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.74
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs192416474; hg19: chr19-1399201;