NM_000156.6:c.227C>T

Variant names:

• chr19-1399893-G-A
• rs150338273
• NM_000156.6:c.227C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4 BS1_Supporting BS2

The NM_000156.6(GAMT):​c.227C>T​(p.Ser76Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00051 in 1,608,680 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S76P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 6.65
• Publications: 12 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000156.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.2776612).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000525 (764/1456374) while in subpopulation NFE AF = 0.000668 (742/1110366). AF 95% confidence interval is 0.000628. There are 2 homozygotes in GnomAdExome4. There are 401 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.227C>T	p.Ser76Leu	missense	Exon 2 of 6	NP_000147.1
	GAMT	NM_138924.3		c.227C>T	p.Ser76Leu	missense	Exon 2 of 5	NP_620279.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.227C>T	p.Ser76Leu	missense	Exon 2 of 6	ENSP00000252288.1
	GAMT	ENST00000902474.1		c.497C>T	p.Ser166Leu	missense	Exon 2 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.227C>T	p.Ser76Leu	missense	Exon 2 of 5	ENSP00000403536.2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000254 AC: 61 AN: 239916 AF XY: 0.000230

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000518

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000525 AC: 764 AN: 1456374 Hom.: 2 Cov.: 33 AF XY: 0.000554 AC XY: 401 AN XY: 723976

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0000905 AC: 4 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 85172

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000668 AC: 742 AN: 1110366

Other (OTH) AF: 0.000266 AC: 16 AN: 60188

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74476

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000458 AC: 7 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.000647 AC: 44 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000558 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000265 AC: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Deficiency of guanidinoacetate methyltransferase (4)
-	4	-	not provided (4)
-	1	-	Cerebral creatine deficiency syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.7
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.032	D
Polyphen		0.66	P
Vest4		0.43
MVP		0.95
MPC		0.14
ClinPred		0.15	T
GERP RS		3.2
PromoterAI		-0.034	Neutral
Varity_R		0.21
gMVP		0.68
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs150338273; hg19: chr19-1399892; COSMIC: COSV52041554; COSMIC: COSV52041554;