chr15-79845217-G-A

Position:

• chr15-79845217-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006441.4(MTHFS):​c.605C>T​(p.Thr202Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T202A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFS NM_006441.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07052523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.605C>T	p.Thr202Ile	missense_variant	3/3	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.533C>T	p.Thr178Ile	missense_variant	4/4		NP_001186689.1
MTHFS	NM_001199758.1	c.434C>T	p.Thr145Ile	missense_variant	3/3		NP_001186687.1
MTHFS	NR_037654.2	n.712C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.605C>T	p.Thr202Ile	missense_variant	3/3	1	NM_006441.4	ENSP00000258874	P1
MTHFS	ENST00000559722.2	c.692C>T	p.Thr231Ile	missense_variant	3/3	2		ENSP00000489076
MTHFS	ENST00000560261.1	c.113C>T	p.Thr38Ile	missense_variant, NMD_transcript_variant	1/4	3		ENSP00000454318

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MTHFS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 202 of the MTHFS protein (p.Thr202Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.26	T;T;.;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.071	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.072	T;.;.;T
Sift4G	Benign	0.071	T;D;T;T
Polyphen		0.013	B;.;.;.
Vest4		0.091
MutPred		0.25		Loss of sheet (P = 0.0084);.;.;.;
MVP		0.18
MPC		0.26
ClinPred		0.052	T
GERP RS		3.4
Varity_R		0.031
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-80137559;