Genetic Variant SHMT1:c.-20+2729C>G (chr17-18360643-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.-20+2729C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 152,022 control chromosomes in the GnomAD database, including 33,933 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 ( 33918 hom., cov: 31)

Exomes 𝑓: 0.64 ( 15 hom. )

Consequence

SHMT1
NM_004169.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.51

Publications

20 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 (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
SHMT1	NM_004169.5	MANE Select	c.-20+2729C>G	intron	N/A	NP_004160.3
SHMT1	NM_148918.3		c.-20+2729C>G	intron	N/A	NP_683718.1
SHMT1	NM_001281786.2		c.-318+2729C>G	intron	N/A	NP_001268715.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SHMT1	ENST00000316694.8	TSL:1 MANE Select	c.-20+2729C>G	intron	N/A	ENSP00000318868.3
SHMT1	ENST00000583780.2	TSL:1	c.-158-91C>G	intron	N/A	ENSP00000462041.2
SHMT1	ENST00000354098.7	TSL:1	c.-20+2729C>G	intron	N/A	ENSP00000318805.3

Frequencies

GnomAD3 genomes

AF:

0.664

AC:

100847

AN:

151834

Hom.:

33872

Cov.:

show subpopulations

Gnomad AFR

AF:

0.753

Gnomad AMI

AF:

0.517

Gnomad AMR

AF:

0.659

Gnomad ASJ

AF:

0.675

Gnomad EAS

AF:

0.535

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.651

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.635

Gnomad OTH

AF:

0.655

GnomAD4 exome

AF:

0.639

AC:

AN:

Hom.:

AF XY:

0.646

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.673

AC:

AN:

Other (OTH)

AF:

0.375

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.664

AC:

100959

AN:

151950

Hom.:

33918

Cov.:

AF XY:

0.661

AC XY:

49079

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.754

AC:

31245

AN:

41446

American (AMR)

AF:

0.659

AC:

10041

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

2343

AN:

3472

East Asian (EAS)

AF:

0.536

AC:

2759

AN:

5148

South Asian (SAS)

AF:

0.523

AC:

2518

AN:

4818

European-Finnish (FIN)

AF:

0.651

AC:

6870

AN:

10546

Middle Eastern (MID)

AF:

0.602

AC:

177

AN:

294

European-Non Finnish (NFE)

AF:

0.635

AC:

43161

AN:

67982

Other (OTH)

AF:

0.653

AC:

1376

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1698

3395

5093

6790

8488

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:

0.547

Hom.:

1524

Bravo

AF:

0.668

Asia WGS

AF:

0.513

AC:

1787

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.45

(source)

DANN

Benign

0.35

PhyloP100

-1.5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over