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GeneBe

rs1979277

Variant summary

Our verdict is Benign. Variant got -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. 12/19 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

2
12

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]

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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 UniProt
SHMT1NM_004169.5 linkuse as main transcriptc.1420C>T p.Leu474Phe missense_variant 12/12 ENST00000316694.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SHMT1ENST00000316694.8 linkuse as main transcriptc.1420C>T p.Leu474Phe missense_variant 12/121 NM_004169.5 P1P34896-1

Frequencies

GnomAD3 genomes
AF:
0.305
AC:
46364
AN:
151908
Hom.:
7394
Cov.:
32
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.:
38
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.:
32
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 providedcase-controlDepartment 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
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

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

Other links and lift over

dbSNP: rs1979277; hg19: chr17-18232096; COSMIC: COSV57398136; COSMIC: COSV57398136; API