rs17284990

Variant names:

• chr15-79851855-T-C
• rs17284990
• NM_006441.4:c.380-6413A>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.380-6413A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,128 control chromosomes in the GnomAD database, including 3,046 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 0.18 (3046 hom., cov: 32)
• Consequence: MTHFS NM_006441.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.280
• Publications: 8 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 = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFS	NM_006441.4	c.380-6413A>G		intron_variant	Intron 2 of 2	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2	c.308-6413A>G		intron_variant	Intron 3 of 3		NP_001186689.1
MTHFS	NM_001199758.1	c.209-6413A>G		intron_variant	Intron 2 of 2		NP_001186687.1
MTHFS	NR_037654.2	n.487-6413A>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4	c.380-6413A>G		intron_variant	Intron 2 of 2	1	NM_006441.4	ENSP00000258874.4
ST20-MTHFS	ENST00000479961.1	c.308-6413A>G		intron_variant	Intron 3 of 3	3		ENSP00000455643.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27991 AN: 152010 Hom.: 3047 Cov.: 32

Gnomad AFR AF: 0.0939

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0603

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.184 AC: 27983 AN: 152128 Hom.: 3046 Cov.: 32 AF XY: 0.185 AC XY: 13766 AN XY: 74366

African (AFR) AF: 0.0937 AC: 3889 AN: 41508

American (AMR) AF: 0.196 AC: 2997 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3470

East Asian (EAS) AF: 0.0600 AC: 311 AN: 5180

South Asian (SAS) AF: 0.262 AC: 1260 AN: 4818

European-Finnish (FIN) AF: 0.302 AC: 3197 AN: 10584

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.225 AC: 15263 AN: 67970

Other (OTH) AF: 0.184 AC: 389 AN: 2112

Alfa AF: 0.212 Hom.: 5898

Bravo AF: 0.172

Asia WGS AF: 0.165 AC: 573 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	1.6
DANN	Benign	0.63
PhyloP100		-0.28
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: rs17284990; hg19: chr15-80144197;