12-57231530-A-G

Position:

• chr12-57231530-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005412.6(SHMT2):​c.281A>G​(p.Asn94Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SHMT2 NM_005412.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

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]

SHMT2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHMT2	NM_005412.6	c.281A>G	p.Asn94Ser	missense_variant	3/12	ENST00000328923.8	NP_005403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHMT2	ENST00000328923.8	c.281A>G	p.Asn94Ser	missense_variant	3/12	1	NM_005412.6	ENSP00000333667.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;.;D;D;.;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.92
MutPred		0.79		Gain of catalytic residue at L92 (P = 0);Gain of catalytic residue at L92 (P = 0);Gain of catalytic residue at L92 (P = 0);.;.;.;.;.;.;.;.;.;.;
MVP		0.87
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-57625313;