Variant chr17-18328782-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000316694.8(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
ENST00000316694.8 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.551

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 made for transcript

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	Protein	UniProt
SHMT1	NM_004169.5 linkuse as main transcript	c.1420C>T	p.Leu474Phe	missense_variant	12/12	ENST00000316694.8	NP_004160.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHMT1	ENST00000316694.8 linkuse as main transcript	c.1420C>T	p.Leu474Phe	missense_variant	12/12	1	NM_004169.5	ENSP00000318868	P1	P34896-1

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

GnomAD3 exomes

AF:

0.268

AC:

58787

AN:

219198

Hom.:

8365

AF XY:

0.265

AC XY:

31436

AN XY:

118586

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 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.:

AF XY:

0.296

AC XY:

211726

AN XY:

715842

show subpopulations

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.:

AF XY:

0.300

AC XY:

22326

AN XY:

74318

show subpopulations

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

LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

2.0

.;M;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.81

.;N;N

REVEL

Benign

0.051

Sift

Benign

0.048

.;D;D

Sift4G

Uncertain

0.024

D;D;D

Polyphen

0.0, 0.17

.;B;B

Vest4

0.10

MPC

0.20

ClinPred

0.012

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over