rs13306567

Positions:

• chr1-11800408-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.476-86G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 969,490 control chromosomes in the GnomAD database, including 1,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (153 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1012 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-11800408-C-G is Benign according to our data. Variant chr1-11800408-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1300897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.476-86G>C		intron_variant		ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.476-86G>C		intron_variant		1	NM_005957.5	ENSP00000365775	A1

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5646 AN: 152164 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.0416

GnomAD4 exome AF: 0.0455 AC: 37172 AN: 817208 Hom.: 1012 Cov.: 11 AF XY: 0.0458 AC XY: 19784 AN XY: 432046

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0279

Gnomad4 ASJ exome AF: 0.0494

Gnomad4 EAS exome AF: 0.00492

Gnomad4 SAS exome AF: 0.0379

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.0529

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.0371 AC: 5651 AN: 152282 Hom.: 153 Cov.: 32 AF XY: 0.0372 AC XY: 2768 AN XY: 74472

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.0317

Gnomad4 NFE AF: 0.0543

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0374 Hom.: 19

Bravo AF: 0.0363

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs13306567; hg19: chr1-11860465;