rs13306567

Variant names:

• chr1-11800408-C-G
• rs13306567
• NM_005957.5:c.476-86G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.476-86G>C		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.599-86G>C		intron	N/A	NP_001317287.1
	MTHFR	NM_001410750.1		c.596-86G>C		intron	N/A	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.476-86G>C		intron	N/A	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.596-86G>C		intron	N/A	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.476-86G>C		intron	N/A	ENSP00000365777.1

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

African (AFR) AF: 0.0104 AC: 220 AN: 21098

American (AMR) AF: 0.0279 AC: 1200 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1085 AN: 21958

East Asian (EAS) AF: 0.00492 AC: 180 AN: 36560

South Asian (SAS) AF: 0.0379 AC: 2773 AN: 73138

European-Finnish (FIN) AF: 0.0314 AC: 1594 AN: 50842

Middle Eastern (MID) AF: 0.115 AC: 515 AN: 4468

European-Non Finnish (NFE) AF: 0.0529 AC: 27866 AN: 527092

Other (OTH) AF: 0.0445 AC: 1739 AN: 39112

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

African (AFR) AF: 0.0109 AC: 452 AN: 41546

American (AMR) AF: 0.0405 AC: 620 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5190

South Asian (SAS) AF: 0.0419 AC: 202 AN: 4824

European-Finnish (FIN) AF: 0.0317 AC: 336 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0543 AC: 3692 AN: 68020

Other (OTH) AF: 0.0450 AC: 95 AN: 2112

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 16, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.44
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs13306567; hg19: chr1-11860465;