chr17-18328782-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/21 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

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.551

Publications

266 publications found

Variant links:

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]

SHMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004169.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHMT1	NM_004169.5	MANE Select	c.1420C>T	p.Leu474Phe	missense	Exon 12 of 12	NP_004160.3
SHMT1	NM_148918.3		c.1303C>T	p.Leu435Phe	missense	Exon 11 of 11	NP_683718.1
SHMT1	NM_001281786.2		c.1006C>T	p.Leu336Phe	missense	Exon 11 of 11	NP_001268715.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHMT1	ENST00000316694.8	TSL:1 MANE Select	c.1420C>T	p.Leu474Phe	missense	Exon 12 of 12	ENSP00000318868.3
SHMT1	ENST00000583780.2	TSL:1	c.1420C>T	p.Leu474Phe	missense	Exon 13 of 13	ENSP00000462041.2
SHMT1	ENST00000354098.7	TSL:1	c.1303C>T	p.Leu435Phe	missense	Exon 11 of 11	ENSP00000318805.3

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46364

AN:

151908

Hom.:

7394

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.268

AC:

58787

AN:

219198

AF XY:

0.265

show subpopulations

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 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.:

AF XY:

0.296

AC XY:

211726

AN XY:

715842

show subpopulations

African (AFR)

AF:

0.344

AC:

11362

AN:

33062

American (AMR)

AF:

0.234

AC:

9886

AN:

42198

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

8381

AN:

25766

East Asian (EAS)

AF:

0.0806

AC:

3157

AN:

39154

South Asian (SAS)

AF:

0.183

AC:

15426

AN:

84126

European-Finnish (FIN)

AF:

0.338

AC:

17594

AN:

52016

Middle Eastern (MID)

AF:

0.263

AC:

1206

AN:

4582

European-Non Finnish (NFE)

AF:

0.316

AC:

348227

AN:

1101814

Other (OTH)

AF:

0.292

AC:

17336

AN:

59454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17752

35504

53255

71007

88759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11332

22664

33996

45328

56660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.305

AC:

46403

AN:

152026

Hom.:

7397

Cov.:

AF XY:

0.300

AC XY:

22326

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.345

AC:

14309

AN:

41434

American (AMR)

AF:

0.248

AC:

3787

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1134

AN:

3470

East Asian (EAS)

AF:

0.0744

AC:

385

AN:

5176

South Asian (SAS)

AF:

0.187

AC:

902

AN:

4824

European-Finnish (FIN)

AF:

0.324

AC:

3432

AN:

10582

Middle Eastern (MID)

AF:

0.293

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.316

AC:

21465

AN:

67950

Other (OTH)

AF:

0.290

AC:

612

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1653

3307

4960

6614

8267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.295

Hom.:

12346

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

LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor

Uncertain:1

Department of Pharmacy and Biotechnology, University of Bologna

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:case-control

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.93

MutationAssessor

Benign

2.0

PhyloP100

0.55

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.81

REVEL

Benign

0.051

Sift

Benign

0.048

Sift4G

Uncertain

0.024

Polyphen

0.0

Vest4

0.10

MPC

0.20

ClinPred

0.012

GERP RS

-4.5

Varity_R

0.071

gMVP

0.28

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over