rs2586179

Variant names:

• chr15-79895664-G-T
• rs2586179
• NM_006441.4:c.117+1208C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 4 publications found

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]

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]

ENSG00000286813 (HGNC:):

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.117+1208C>A		intron_variant	Intron 1 of 2	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.46-6310C>A		intron_variant	Intron 2 of 3		NP_001186689.1
MTHFS	NM_001199758.1	c.-55+1497C>A		intron_variant	Intron 1 of 2		NP_001186687.1
MTHFS	NR_037654.2	n.224+1127C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.117+1208C>A		intron_variant	Intron 1 of 2	1	NM_006441.4	ENSP00000258874.4
ST20-MTHFS	ENST00000479961.1	c.46-6310C>A		intron_variant	Intron 2 of 3	3		ENSP00000455643.1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68342 AN: 151918 Hom.: 16121 Cov.: 33

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.: 33 AF XY: 0.448 AC XY: 33314 AN XY: 74294

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.41
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2586179; hg19: chr15-80188006;