Genetic Variant NM_006441.4:c.117+1208C>A (chr15-79895664-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_006441.4(MTHFS):c.117+1208C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,034 control chromosomes in the GnomAD database, including 16,136 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 0.45 ( 16136 hom., cov: 33)

Consequence

MTHFS
NM_006441.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.37

Publications

4 publications found

Variant links:

Genes affected

MTHFS (HGNC:7437): (methenyltetrahydrofolate synthetase) The protein encoded by this gene is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates involved in 1-carbon metabolism. An increased activity of the encoded protein can result in an increased folate turnover rate and folate depletion. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

MTHFS links:

ST20-MTHFS (HGNC:44655): (ST20-MTHFS readthrough) This locus represents naturally occurring read-through transcription between the neighboring suppressor of tumorigenicity 20 and 5,10-methenyltetrahydrofolate synthetase (5-formyltetrahydrofolate cyclo-ligase) genes on chromosome 15. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

ST20-MTHFS links:

ENSG00000286813 (HGNC:):

ENSG00000286813 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=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006441.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFS	NM_006441.4	MANE Select	c.117+1208C>A	intron	N/A	NP_006432.1
ST20-MTHFS	NM_001199760.2		c.46-6310C>A	intron	N/A	NP_001186689.1
MTHFS	NM_001199758.1		c.-55+1497C>A	intron	N/A	NP_001186687.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFS	ENST00000258874.4	TSL:1 MANE Select	c.117+1208C>A	intron	N/A	ENSP00000258874.4
ST20-MTHFS	ENST00000479961.1	TSL:3	c.46-6310C>A	intron	N/A	ENSP00000455643.1
MTHFS	ENST00000559722.2	TSL:2	c.204+1497C>A	intron	N/A	ENSP00000489076.1

Frequencies

GnomAD3 genomes

AF:

0.450

AC:

68342

AN:

151918

Hom.:

16121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.478

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.399

Gnomad FIN

AF:

0.469

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.522

Gnomad OTH

AF:

0.468

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.450

AC:

68379

AN:

152034

Hom.:

16136

Cov.:

AF XY:

0.448

AC XY:

33314

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.307

AC:

12734

AN:

41466

American (AMR)

AF:

0.478

AC:

7302

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1873

AN:

3470

East Asian (EAS)

AF:

0.470

AC:

2437

AN:

5184

South Asian (SAS)

AF:

0.399

AC:

1923

AN:

4816

European-Finnish (FIN)

AF:

0.469

AC:

4947

AN:

10546

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.522

AC:

35471

AN:

67960

Other (OTH)

AF:

0.467

AC:

987

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1928

3857

5785

7714

9642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.498

Hom.:

6585

Bravo

AF:

0.442

Asia WGS

AF:

0.455

AC:

1581

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.20

(source)

DANN

Benign

0.41

PhyloP100

-1.4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over