12-57229580-A-G

Position:

• chr12-57229580-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000556825.5(SHMT2):​n.-199A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 650,854 control chromosomes in the GnomAD database, including 1,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (322 hom., cov: 33)
  • Exomes 𝑓: 0.062 (1292 hom.)
• Consequence: SHMT2 ENST00000556825.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0580

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]

ENSG00000276727 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-57229580-A-G is Benign according to our data. Variant chr12-57229580-A-G is described in ClinVar as [Benign]. Clinvar id is 1290032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.57229580A>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHMT2	ENST00000556825.5	n.-199A>G		non_coding_transcript_exon_variant	1/11	1		ENSP00000451169.1
SHMT2	ENST00000556825.5	n.-199A>G		5_prime_UTR_variant	1/11	1		ENSP00000451169.1
ENSG00000276727	ENST00000617433.1	n.619T>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8150 AN: 152214 Hom.: 324 Cov.: 33

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.0833

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0716

GnomAD4 exome AF: 0.0616 AC: 30720 AN: 498522 Hom.: 1292 Cov.: 6 AF XY: 0.0619 AC XY: 16315 AN XY: 263604

Gnomad4 AFR exome AF: 0.0317

Gnomad4 AMR exome AF: 0.0567

Gnomad4 ASJ exome AF: 0.0771

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.0776

Gnomad4 NFE exome AF: 0.0480

Gnomad4 OTH exome AF: 0.0678

GnomAD4 genome AF: 0.0534 AC: 8139 AN: 152332 Hom.: 322 Cov.: 33 AF XY: 0.0566 AC XY: 4216 AN XY: 74490

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.0738

Gnomad4 FIN AF: 0.0833

Gnomad4 NFE AF: 0.0468

Gnomad4 OTH AF: 0.0709

Alfa AF: 0.0512 Hom.: 46

Bravo AF: 0.0520

Asia WGS AF: 0.129 AC: 448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.7
DANN	Benign	0.57

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

LitVar

Other links and lift over

dbSNP: rs28365862; hg19: chr12-57623363;