Genetic Variant SHMT1:c.1054+141C>T (chr17-18333025-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_004169.5(SHMT1):c.1054+141C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,087,362 control chromosomes in the GnomAD database, including 30,478 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 0.22 ( 3856 hom., cov: 33)

Exomes 𝑓: 0.24 ( 26622 hom. )

Consequence

SHMT1
NM_004169.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.678

Publications

7 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHMT1	NM_004169.5 link	c.1054+141C>T		intron_variant	Intron 9 of 11	ENST00000316694.8	NP_004160.3	P34896-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHMT1	ENST00000316694.8 link	c.1054+141C>T		intron_variant	Intron 9 of 11	1	NM_004169.5	ENSP00000318868.3		P34896-1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33336

AN:

152122

Hom.:

3850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.260

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.179

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.225

GnomAD2 exomes

AF:

0.238

AC:

42390

AN:

178122

AF XY:

0.237

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.245

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.236

AC:

220722

AN:

935122

Hom.:

26622

Cov.:

AF XY:

0.235

AC XY:

113128

AN XY:

482062

show subpopulations

African (AFR)

AF:

0.152

AC:

3524

AN:

23120

American (AMR)

AF:

0.248

AC:

9202

AN:

37090

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

5981

AN:

22314

East Asian (EAS)

AF:

0.247

AC:

8546

AN:

34634

South Asian (SAS)

AF:

0.193

AC:

13851

AN:

71918

European-Finnish (FIN)

AF:

0.262

AC:

9801

AN:

37444

Middle Eastern (MID)

AF:

0.285

AC:

1362

AN:

4772

European-Non Finnish (NFE)

AF:

0.239

AC:

158122

AN:

660484

Other (OTH)

AF:

0.238

AC:

10333

AN:

43346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

8536

17073

25609

34146

42682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4192

8384

12576

16768

20960

<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:

0.219

AC:

33360

AN:

152240

Hom.:

3856

Cov.:

AF XY:

0.218

AC XY:

16255

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.152

AC:

6312

AN:

41560

American (AMR)

AF:

0.239

AC:

3649

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

904

AN:

3472

East Asian (EAS)

AF:

0.297

AC:

1535

AN:

5168

South Asian (SAS)

AF:

0.180

AC:

868

AN:

4824

European-Finnish (FIN)

AF:

0.275

AC:

2919

AN:

10598

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16492

AN:

68006

Other (OTH)

AF:

0.223

AC:

472

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1353

2705

4058

5410

6763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.228

Hom.:

783

Bravo

AF:

0.220

Asia WGS

AF:

0.199

AC:

693

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

7.5

(source)

DANN

Benign

0.66

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over