rs13306553

Variant names:

• chr1-11800060-A-G
• rs13306553
• NM_005957.5:c.586+152T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005957.5(MTHFR):​c.586+152T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 751,876 control chromosomes in the GnomAD database, including 4,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (806 hom., cov: 30)
  • Exomes 𝑓: 0.10 (3426 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.183
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-11800060-A-G is Benign according to our data. Variant chr1-11800060-A-G is described in ClinVar as Benign. ClinVar VariationId is 1295236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.586+152T>C		intron_variant	Intron 4 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.586+152T>C		intron_variant	Intron 4 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.0994 AC: 15112 AN: 151982 Hom.: 809 Cov.: 30

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0827

GnomAD4 exome AF: 0.102 AC: 61121 AN: 599776 Hom.: 3426 Cov.: 6 AF XY: 0.104 AC XY: 33899 AN XY: 326380

African (AFR) AF: 0.0944 AC: 1615 AN: 17100

American (AMR) AF: 0.0644 AC: 2641 AN: 41020

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 714 AN: 20230

East Asian (EAS) AF: 0.103 AC: 3546 AN: 34418

South Asian (SAS) AF: 0.143 AC: 9655 AN: 67716

European-Finnish (FIN) AF: 0.112 AC: 4388 AN: 39268

Middle Eastern (MID) AF: 0.0463 AC: 116 AN: 2506

European-Non Finnish (NFE) AF: 0.102 AC: 35138 AN: 345532

Other (OTH) AF: 0.103 AC: 3308 AN: 31986

GnomAD4 genome AF: 0.0993 AC: 15109 AN: 152100 Hom.: 806 Cov.: 30 AF XY: 0.100 AC XY: 7460 AN XY: 74366

African (AFR) AF: 0.0944 AC: 3919 AN: 41506

American (AMR) AF: 0.0685 AC: 1047 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.122 AC: 627 AN: 5156

South Asian (SAS) AF: 0.158 AC: 759 AN: 4818

European-Finnish (FIN) AF: 0.127 AC: 1345 AN: 10584

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7067 AN: 67968

Other (OTH) AF: 0.0828 AC: 175 AN: 2114

Alfa AF: 0.0997 Hom.: 134

Bravo AF: 0.0928

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.82
DANN	Benign	0.69
PhyloP100		-0.18
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: rs13306553; hg19: chr1-11860117;