rs2461838

Variant names:

• chr17-18361950-G-A
• rs2461838
• NM_004169.5:c.-20+1422C>T

Variant summary

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

The NM_004169.5(SHMT1):​c.-20+1422C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,014 control chromosomes in the GnomAD database, including 5,284 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 0.26 (5284 hom., cov: 32)
• Consequence: SHMT1 NM_004169.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 21 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHMT1	NM_004169.5	c.-20+1422C>T		intron_variant	Intron 1 of 11	ENST00000316694.8	NP_004160.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHMT1	ENST00000316694.8	c.-20+1422C>T		intron_variant	Intron 1 of 11	1	NM_004169.5	ENSP00000318868.3

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38874 AN: 151896 Hom.: 5285 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.0678

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.256

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

GnomAD4 genome AF: 0.256 AC: 38887 AN: 152014 Hom.: 5284 Cov.: 32 AF XY: 0.251 AC XY: 18648 AN XY: 74272

African (AFR) AF: 0.213 AC: 8823 AN: 41466

American (AMR) AF: 0.224 AC: 3419 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3472

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

South Asian (SAS) AF: 0.176 AC: 848 AN: 4810

European-Finnish (FIN) AF: 0.288 AC: 3032 AN: 10530

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20406 AN: 67968

Other (OTH) AF: 0.253 AC: 532 AN: 2104

Alfa AF: 0.278 Hom.: 7918

Bravo AF: 0.246

Asia WGS AF: 0.132 AC: 460 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.21
DANN	Benign	0.49
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2461838; hg19: chr17-18265264; COSMIC: COSV57398260;