15-79889117-C-A

Variant names:

• chr15-79889117-C-A
• rs145953716
• NM_006441.4:c.355G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006441.4(MTHFS):​c.355G>T​(p.Val119Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. V119L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFS NM_006441.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.727
• Publications: 5 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07673249).

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.355G>T	p.Val119Phe	missense	Exon 2 of 3	NP_006432.1	P49914-1
	ST20-MTHFS	NM_001199760.2		c.283G>T	p.Val95Phe	missense	Exon 3 of 4	NP_001186689.1	A0A0A6YYL1
	MTHFS	NM_001199758.1		c.184G>T	p.Val62Phe	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.355G>T	p.Val119Phe	missense	Exon 2 of 3	ENSP00000258874.4	P49914-1
	ST20-MTHFS	ENST00000479961.1	TSL:3	c.283G>T	p.Val95Phe	missense	Exon 3 of 4	ENSP00000455643.1
	MTHFS	ENST00000559722.2	TSL:2	c.442G>T	p.Val148Phe	missense	Exon 2 of 3	ENSP00000489076.1	A0A0U1RQM3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.73
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.041
Sift	Benign	0.055	T
Sift4G	Uncertain	0.059	T
Polyphen		0.14	B
Vest4		0.19
MutPred		0.46		Gain of disorder (P = 0.2052)
MVP		0.29
MPC		0.36
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145953716; hg19: chr15-80181459;