12-57231494-G-T

Variant names:

• chr12-57231494-G-T
• NM_005412.6:c.245G>T

Variant summary

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

The NM_005412.6(SHMT2):​c.245G>T​(p.Arg82Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,798 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: 0.0000055 (0 hom.)
• Consequence: SHMT2 NM_005412.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.08

Genes affected

SHMT2 (HGNC:10852): (serine hydroxymethyltransferase 2) This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

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
SHMT2	NM_005412.6	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 12	ENST00000328923.8	NP_005403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHMT2	ENST00000328923.8	c.245G>T	p.Arg82Leu	missense_variant	Exon 3 of 12	1	NM_005412.6	ENSP00000333667.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727200

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245G>T (p.R82L) alteration is located in exon 3 (coding exon 3) of the SHMT2 gene. This alteration results from a G to T substitution at nucleotide position 245, causing the arginine (R) at amino acid position 82 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;.;D;.;D;D;.;D;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.93	P;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.84
MutPred		0.50		Gain of catalytic residue at N78 (P = 6e-04);Gain of catalytic residue at N78 (P = 6e-04);Gain of catalytic residue at N78 (P = 6e-04);.;.;.;.;.;.;.;.;.;.;
MVP		0.68
MPC		0.70
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.81

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: chr12-57625277;