rs142339581

Variant names:

• chr15-79889113-C-A
• rs142339581
• NM_006441.4:c.359G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-79889113-C-A
• chr15-79889113-C-G
• chr15-79889113-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006441.4(MTHFS):​c.359G>T​(p.Arg120Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MTHFS NM_006441.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.33
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFS	NM_006441.4	MANE Select	c.359G>T	p.Arg120Leu	missense	Exon 2 of 3	NP_006432.1	P49914-1
	ST20-MTHFS	NM_001199760.2		c.287G>T	p.Arg96Leu	missense	Exon 3 of 4	NP_001186689.1	A0A0A6YYL1
	MTHFS	NM_001199758.1		c.188G>T	p.Arg63Leu	missense	Exon 2 of 3	NP_001186687.1	P49914

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFS	ENST00000258874.4	TSL:1 MANE Select	c.359G>T	p.Arg120Leu	missense	Exon 2 of 3	ENSP00000258874.4	P49914-1
	ST20-MTHFS	ENST00000479961.1	TSL:3	c.287G>T	p.Arg96Leu	missense	Exon 3 of 4	ENSP00000455643.1
	MTHFS	ENST00000559722.2	TSL:2	c.446G>T	p.Arg149Leu	missense	Exon 2 of 3	ENSP00000489076.1	A0A0U1RQM3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.016	D
Sift4G	Benign	0.064	T
Polyphen		0.94	P
Vest4		0.30
MutPred		0.64		Loss of disorder (P = 0.0907)
MVP		0.55
MPC		0.62
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.77

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: rs142339581; hg19: chr15-80181455; COSMIC: COSV99358304;