NM_006441.4:c.380-1411T>G

Variant names:

• chr15-79846853-A-C
• rs622506
• NM_006441.4:c.380-1411T>G

Variant summary

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

The NM_006441.4(MTHFS):​c.380-1411T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,068 control chromosomes in the GnomAD database, including 9,574 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 0.34 (9574 hom., cov: 33)
• Consequence: MTHFS NM_006441.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.380-1411T>G		intron_variant	Intron 2 of 2	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.308-1411T>G		intron_variant	Intron 3 of 3		NP_001186689.1
MTHFS	NM_001199758.1	c.209-1411T>G		intron_variant	Intron 2 of 2		NP_001186687.1
MTHFS	NR_037654.2	n.487-1411T>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.380-1411T>G		intron_variant	Intron 2 of 2	1	NM_006441.4	ENSP00000258874.4
ST20-MTHFS	ENST00000479961.1	c.308-1411T>G		intron_variant	Intron 3 of 3	3		ENSP00000455643.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51422 AN: 151950 Hom.: 9572 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51438 AN: 152068 Hom.: 9574 Cov.: 33 AF XY: 0.342 AC XY: 25448 AN XY: 74318

African (AFR) AF: 0.191 AC: 7943 AN: 41498

American (AMR) AF: 0.420 AC: 6425 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3472

East Asian (EAS) AF: 0.449 AC: 2323 AN: 5172

South Asian (SAS) AF: 0.472 AC: 2273 AN: 4812

European-Finnish (FIN) AF: 0.433 AC: 4575 AN: 10554

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.376 AC: 25558 AN: 67960

Other (OTH) AF: 0.332 AC: 701 AN: 2114

Alfa AF: 0.325 Hom.: 1279

Bravo AF: 0.331

Asia WGS AF: 0.445 AC: 1545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.44
PhyloP100		-0.12
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: rs622506; hg19: chr15-80139195;