rs1426413125

Variant names:

• chr12-57231870-C-A
• NM_005412.6:c.469C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57231870-C-A
• chr12-57231870-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_005412.6(SHMT2):​c.469C>A​(p.Pro157Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SHMT2 NM_005412.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57231870-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHMT2	NM_005412.6	c.469C>A	p.Pro157Thr	missense_variant	Exon 4 of 12	ENST00000328923.8	NP_005403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHMT2	ENST00000328923.8	c.469C>A	p.Pro157Thr	missense_variant	Exon 4 of 12	1	NM_005412.6	ENSP00000333667.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461298 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726892

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;.;D;D;.;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.3	M;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.077	T;T;T;T;D;D;D;D;T;D;D;T;D
Sift4G	Benign	0.075	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.68		Gain of catalytic residue at D159 (P = 0.0594);Gain of catalytic residue at D159 (P = 0.0594);Gain of catalytic residue at D159 (P = 0.0594);.;.;.;.;.;.;.;.;.;.;
MVP		0.83
MPC		1.5
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.89

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: chr12-57625653;