rs1113983

Variant names:

• chr15-79874255-C-A
• rs1113983
• NM_006441.4:c.379+14838G>T

Variant summary

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

The NM_006441.4(MTHFS):​c.379+14838G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 151,532 control chromosomes in the GnomAD database, including 14,086 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 0.42 (14086 hom., cov: 32)
• Consequence: MTHFS NM_006441.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 10 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 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.379+14838G>T		intron	N/A	NP_006432.1	P49914-1
	ST20-MTHFS	NM_001199760.2		c.307+14838G>T		intron	N/A	NP_001186689.1	A0A0A6YYL1
	MTHFS	NM_001199758.1		c.208+14838G>T		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.379+14838G>T		intron	N/A	ENSP00000258874.4	P49914-1
	ST20-MTHFS	ENST00000479961.1	TSL:3	c.307+14838G>T		intron	N/A	ENSP00000455643.1
	MTHFS	ENST00000559722.2	TSL:2	c.466+14838G>T		intron	N/A	ENSP00000489076.1	A0A0U1RQM3

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64205 AN: 151414 Hom.: 14055 Cov.: 32

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.402

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

GnomAD4 genome AF: 0.424 AC: 64281 AN: 151532 Hom.: 14086 Cov.: 32 AF XY: 0.428 AC XY: 31653 AN XY: 74028

African (AFR) AF: 0.504 AC: 20772 AN: 41206

American (AMR) AF: 0.418 AC: 6345 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1148 AN: 3390

East Asian (EAS) AF: 0.537 AC: 2772 AN: 5166

South Asian (SAS) AF: 0.529 AC: 2550 AN: 4822

European-Finnish (FIN) AF: 0.411 AC: 4335 AN: 10542

Middle Eastern (MID) AF: 0.465 AC: 134 AN: 288

European-Non Finnish (NFE) AF: 0.371 AC: 25176 AN: 67930

Other (OTH) AF: 0.401 AC: 838 AN: 2088

Alfa AF: 0.415 Hom.: 2255

Bravo AF: 0.427

Asia WGS AF: 0.488 AC: 1698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.53
DANN	Benign	0.50
PhyloP100		-1.2
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: rs1113983; hg19: chr15-80166597;