Genetic Variant SHMT1:c.-309C>G (chr17-18363661-G-C) – 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.-309C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 152,246 control chromosomes in the GnomAD database, including 34,005 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 0.66 ( 33990 hom., cov: 35)

Exomes 𝑓: 0.72 ( 15 hom. )

Consequence

SHMT1
NM_004169.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.02

Publications

11 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=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.747 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	Effect	Exon Rank	Protein	UniProt
SHMT1	NM_004169.5	MANE Select	c.-309C>G	upstream_gene	N/A	NP_004160.3
SHMT1	NM_148918.3		c.-309C>G	upstream_gene	N/A	NP_683718.1	P34896-2
SHMT1	NM_001281786.2		c.-607C>G	upstream_gene	N/A	NP_001268715.1	P34896-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SHMT1	ENST00000316694.8	TSL:1 MANE Select	c.-309C>G	upstream_gene	N/A	ENSP00000318868.3	P34896-1
SHMT1	ENST00000583780.2	TSL:1	c.-448C>G	upstream_gene	N/A	ENSP00000462041.2	P34896-1
SHMT1	ENST00000354098.7	TSL:1	c.-309C>G	upstream_gene	N/A	ENSP00000318805.3	P34896-2

Frequencies

GnomAD3 genomes

AF:

0.664

AC:

101044

AN:

152070

Hom.:

33944

Cov.:

show subpopulations

Gnomad AFR

AF:

0.754

Gnomad AMI

AF:

0.518

Gnomad AMR

AF:

0.660

Gnomad ASJ

AF:

0.676

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.635

Gnomad OTH

AF:

0.657

GnomAD4 exome

AF:

0.724

AC:

AN:

Hom.:

AF XY:

0.729

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.700

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.665

AC:

101157

AN:

152188

Hom.:

33990

Cov.:

AF XY:

0.661

AC XY:

49211

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.754

AC:

31343

AN:

41546

American (AMR)

AF:

0.660

AC:

10087

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.676

AC:

2345

AN:

3470

East Asian (EAS)

AF:

0.535

AC:

2760

AN:

5162

South Asian (SAS)

AF:

0.523

AC:

2525

AN:

4828

European-Finnish (FIN)

AF:

0.652

AC:

6905

AN:

10598

Middle Eastern (MID)

AF:

0.602

AC:

177

AN:

294

European-Non Finnish (NFE)

AF:

0.635

AC:

43160

AN:

67982

Other (OTH)

AF:

0.655

AC:

1385

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1827

3654

5481

7308

9135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.659

Hom.:

4126

Bravo

AF:

0.668

Asia WGS

AF:

0.511

AC:

1780

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.14

(source)

DANN

Benign

0.29

PhyloP100

-4.0

PromoterAI

-0.089

Neutral

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over