rs1979277

chr17-18328782-G-Achr17-18328782-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004169.5(SHMT1):c.1420C>T(p.Leu474Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,594,198 control chromosomes in the GnomAD database, including 74,438 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L474R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (7397 hom., cov: 32)
  • Exomes 𝑓: 0.30 (67041 hom.)
• Consequence: SHMT1 NM_004169.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.551

Genes affected

SHMT1 (HGNC:10850): (serine hydroxymethyltransferase 1) This gene encodes the cytosolic form of serine hydroxymethyltransferase, a pyridoxal phosphate-containing enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. This reaction provides one-carbon units for synthesis of methionine, thymidylate, and purines in the cytoplasm. This gene is located within the Smith-Magenis syndrome region on chromosome 17. A pseudogene of this gene is located on the short arm of chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005044967).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHMT1	NM_004169.5	c.1420C>T	p.Leu474Phe	missense_variant	12/12	ENST00000316694.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHMT1	ENST00000316694.8	c.1420C>T	p.Leu474Phe	missense_variant	12/12	1	NM_004169.5	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46364 AN: 151908 Hom.: 7394 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.0738

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.293

GnomAD3 exomes AF: 0.268 AC: 58787 AN: 219198 Hom.: 8365 AF XY: 0.265 AC XY: 31436 AN XY: 118586

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.0757

Gnomad SAS exome AF: 0.184

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.300 AC: 432575 AN: 1442172 Hom.: 67041 Cov.: 38 AF XY: 0.296 AC XY: 211726 AN XY: 715842

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.325

Gnomad4 EAS exome AF: 0.0806

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.292

GnomAD4 genome AF: 0.305 AC: 46403 AN: 152026 Hom.: 7397 Cov.: 32 AF XY: 0.300 AC XY: 22326 AN XY: 74318

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.0744

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.290

Alfa AF: 0.310 Hom.: 4490

Bravo AF: 0.297

TwinsUK AF: 0.314 AC: 1163

ALSPAC AF: 0.327 AC: 1260

ESP6500AA AF: 0.337 AC: 1485

ESP6500EA AF: 0.303 AC: 2608

ExAC AF: 0.254 AC: 30698

Asia WGS AF: 0.152 AC: 532 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.30	T
REVEL	Benign	0.051
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.0, 0.17	.;B;B
Vest4		0.10
MPC		0.20
ClinPred		0.012	T
GERP RS		-4.5
Varity_R		0.071
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1979277; hg19: chr17-18232096; COSMIC: COSV57398136; COSMIC: COSV57398136;