rs8923

Positions:

• chr15-79845218-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006441.4(MTHFS):​c.604A>G​(p.Thr202Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,614,148 control chromosomes in the GnomAD database, including 6,373 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.075 (478 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5895 hom.)
• Consequence: MTHFS NM_006441.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.55

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017362237).
• BP6: Variant 15-79845218-T-C is Benign according to our data. Variant chr15-79845218-T-C is described in ClinVar as [Benign]. Clinvar id is 2038284.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.604A>G	p.Thr202Ala	missense_variant	3/3	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.532A>G	p.Thr178Ala	missense_variant	4/4		NP_001186689.1
MTHFS	NM_001199758.1	c.433A>G	p.Thr145Ala	missense_variant	3/3		NP_001186687.1
MTHFS	NR_037654.2	n.711A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.604A>G	p.Thr202Ala	missense_variant	3/3	1	NM_006441.4	ENSP00000258874	P1
MTHFS	ENST00000559722.2	c.691A>G	p.Thr231Ala	missense_variant	3/3	2		ENSP00000489076
MTHFS	ENST00000560261.1	c.112A>G	p.Thr38Ala	missense_variant, NMD_transcript_variant	1/4	3		ENSP00000454318

Frequencies

GnomAD3 genomes AF: 0.0746 AC: 11351 AN: 152178 Hom.: 478 Cov.: 32

Gnomad AFR AF: 0.0710

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.0732

GnomAD3 exomes AF: 0.0666 AC: 16739 AN: 251310 Hom.: 717 AF XY: 0.0674 AC XY: 9159 AN XY: 135816

Gnomad AFR exome AF: 0.0706

Gnomad AMR exome AF: 0.0370

Gnomad ASJ exome AF: 0.0804

Gnomad EAS exome AF: 0.00761

Gnomad SAS exome AF: 0.0353

Gnomad FIN exome AF: 0.0656

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.0712

GnomAD4 exome AF: 0.0863 AC: 126177 AN: 1461852 Hom.: 5895 Cov.: 31 AF XY: 0.0848 AC XY: 61642 AN XY: 727234

Gnomad4 AFR exome AF: 0.0717

Gnomad4 AMR exome AF: 0.0411

Gnomad4 ASJ exome AF: 0.0781

Gnomad4 EAS exome AF: 0.00877

Gnomad4 SAS exome AF: 0.0374

Gnomad4 FIN exome AF: 0.0691

Gnomad4 NFE exome AF: 0.0966

Gnomad4 OTH exome AF: 0.0798

GnomAD4 genome AF: 0.0746 AC: 11358 AN: 152296 Hom.: 478 Cov.: 32 AF XY: 0.0712 AC XY: 5305 AN XY: 74472

Gnomad4 AFR AF: 0.0711

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.0832

Gnomad4 EAS AF: 0.00907

Gnomad4 SAS AF: 0.0356

Gnomad4 FIN AF: 0.0633

Gnomad4 NFE AF: 0.0900

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0855 Hom.: 1539

Bravo AF: 0.0763

TwinsUK AF: 0.0992 AC: 368

ALSPAC AF: 0.0996 AC: 384

ESP6500AA AF: 0.0692 AC: 305

ESP6500EA AF: 0.0887 AC: 763

ExAC AF: 0.0678 AC: 8227

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.0894

EpiControl AF: 0.0884

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0020
DANN	Benign	0.27
DEOGEN2	Benign	0.28	T;.;.;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.19	T;T;.;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.31	N;.;.;N
REVEL	Benign	0.052
Sift	Benign	0.76	T;.;.;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.028
MPC		0.24
ClinPred		0.0029	T
GERP RS		-9.9
Varity_R		0.013
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs8923; hg19: chr15-80137560; COSMIC: COSV51913648; COSMIC: COSV51913648;