15-79843787-A-G

Variant names:

• chr15-79843787-A-G
• rs685487
• NM_006441.4:c.*1423T>C

Variant summary

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

The NM_006441.4(MTHFS):​c.*1423T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,124 control chromosomes in the GnomAD database, including 9,565 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 (9565 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTHFS NM_006441.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.427
• Publications: 17 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]

ENSG00000261229 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.454 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.*1423T>C		3_prime_UTR	Exon 3 of 3	NP_006432.1	P49914-1
	ST20-MTHFS	NM_001199760.2		c.*1423T>C		3_prime_UTR	Exon 4 of 4	NP_001186689.1	A0A0A6YYL1
	MTHFS	NM_001199758.1		c.*1423T>C		3_prime_UTR	Exon 3 of 3	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.*1423T>C		3_prime_UTR	Exon 3 of 3	ENSP00000258874.4	P49914-1
	ENSG00000261229	ENST00000567415.1	TSL:6	n.518T>C		non_coding_transcript_exon	Exon 1 of 1
	MTHFS	ENST00000560261.1	TSL:3	n.*52+1371T>C		intron	N/A	ENSP00000454318.1	H3BMB9

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51419 AN: 152006 Hom.: 9563 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.333

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.338 AC: 51436 AN: 152124 Hom.: 9565 Cov.: 32 AF XY: 0.342 AC XY: 25432 AN XY: 74352

African (AFR) AF: 0.192 AC: 7971 AN: 41526

American (AMR) AF: 0.417 AC: 6379 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3470

East Asian (EAS) AF: 0.449 AC: 2320 AN: 5170

South Asian (SAS) AF: 0.470 AC: 2264 AN: 4814

European-Finnish (FIN) AF: 0.432 AC: 4570 AN: 10572

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25590 AN: 67968

Other (OTH) AF: 0.332 AC: 701 AN: 2112

Alfa AF: 0.362 Hom.: 32880

Bravo AF: 0.332

Asia WGS AF: 0.445 AC: 1544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.74
PhyloP100		-0.43

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs685487; hg19: chr15-80136129;