rs6495446

Variant names:

• chr15-79862640-C-T
• rs6495446
• NM_006441.4:c.380-17198G>A

Variant summary

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

The NM_006441.4(MTHFS):​c.380-17198G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,050 control chromosomes in the GnomAD database, including 7,702 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 0.31 (7702 hom., cov: 32)
• Consequence: MTHFS NM_006441.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 19 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

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.380-17198G>A		intron	N/A	NP_006432.1	P49914-1
	ST20-MTHFS	NM_001199760.2		c.308-17198G>A		intron	N/A	NP_001186689.1	A0A0A6YYL1
	MTHFS	NM_001199758.1		c.209-17198G>A		intron	N/A	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.380-17198G>A		intron	N/A	ENSP00000258874.4	P49914-1
	ST20-MTHFS	ENST00000479961.1	TSL:3	c.308-17198G>A		intron	N/A	ENSP00000455643.1
	MTHFS	ENST00000559722.2	TSL:2	c.467-17198G>A		intron	N/A	ENSP00000489076.1	A0A0U1RQM3

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46712 AN: 151932 Hom.: 7677 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.308 AC: 46766 AN: 152050 Hom.: 7702 Cov.: 32 AF XY: 0.306 AC XY: 22734 AN XY: 74346

African (AFR) AF: 0.428 AC: 17718 AN: 41412

American (AMR) AF: 0.252 AC: 3849 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 876 AN: 3470

East Asian (EAS) AF: 0.239 AC: 1238 AN: 5186

South Asian (SAS) AF: 0.222 AC: 1072 AN: 4826

European-Finnish (FIN) AF: 0.274 AC: 2895 AN: 10574

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18235 AN: 67976

Other (OTH) AF: 0.283 AC: 598 AN: 2112

Alfa AF: 0.274 Hom.: 10521

Bravo AF: 0.314

Asia WGS AF: 0.229 AC: 798 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.12
DANN	Benign	0.48
PhyloP100		-1.1
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: rs6495446; hg19: chr15-80154982;