rs6495446

Positions:

• chr15-79862640-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.380-17198G>A		intron_variant		ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.308-17198G>A		intron_variant			NP_001186689.1
MTHFS	NM_001199758.1	c.209-17198G>A		intron_variant			NP_001186687.1
MTHFS	NR_037654.2	n.487-17198G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.380-17198G>A		intron_variant		1	NM_006441.4	ENSP00000258874	P1
MTHFS	ENST00000559722.2	c.467-17198G>A		intron_variant		2		ENSP00000489076

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

Gnomad4 AFR AF: 0.428

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.283

Alfa AF: 0.271 Hom.: 7502

Bravo AF: 0.314

Asia WGS AF: 0.229 AC: 798 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.12
DANN	Benign	0.48

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: rs6495446; hg19: chr15-80154982;