17-18363725-G-T

Variant names:

• chr17-18363725-G-T
• rs643333
• NM_004169.5:c.-373C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004169.5(SHMT1):​c.-373C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,252 control chromosomes in the GnomAD database, including 4,240 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4240 hom., cov: 33)
• Consequence: SHMT1 NM_004169.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHMT1	NM_004169.5	c.-373C>A		upstream_gene_variant		ENST00000316694.8	NP_004160.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHMT1	ENST00000316694.8	c.-373C>A		upstream_gene_variant		1	NM_004169.5	ENSP00000318868.3

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32045 AN: 152134 Hom.: 4242 Cov.: 33

Gnomad AFR AF: 0.0663

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.0678

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.222

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 32043 AN: 152252 Hom.: 4240 Cov.: 33 AF XY: 0.209 AC XY: 15523 AN XY: 74438

African (AFR) AF: 0.0662 AC: 2750 AN: 41572

American (AMR) AF: 0.207 AC: 3162 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1042 AN: 3470

East Asian (EAS) AF: 0.0683 AC: 354 AN: 5182

South Asian (SAS) AF: 0.176 AC: 850 AN: 4828

European-Finnish (FIN) AF: 0.287 AC: 3042 AN: 10608

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20040 AN: 67986

Other (OTH) AF: 0.220 AC: 464 AN: 2112

Alfa AF: 0.190 Hom.: 589

Bravo AF: 0.195

Asia WGS AF: 0.120 AC: 419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.51
PhyloP100		0.097
PromoterAI		0.018	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs643333; hg19: chr17-18267039;