1-11800063-T-C

Variant names:

• chr1-11800063-T-C
• rs11121832
• NM_005957.5:c.586+149A>G

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+149A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 754,720 control chromosomes in the GnomAD database, including 215,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (42568 hom., cov: 29)
  • Exomes 𝑓: 0.76 (173146 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.906
• Publications: 24 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=-0.87).
• BP6: Variant 1-11800063-T-C is Benign according to our data. Variant chr1-11800063-T-C is described in ClinVar as Benign. ClinVar VariationId is 1295234.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.586+149A>G		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+149A>G		intron_variant	Intron 4 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113330 AN: 151768 Hom.: 42537 Cov.: 29

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.695

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.755 AC: 455218 AN: 602834 Hom.: 173146 Cov.: 6 AF XY: 0.747 AC XY: 244988 AN XY: 327986

African (AFR) AF: 0.689 AC: 11829 AN: 17162

American (AMR) AF: 0.862 AC: 35669 AN: 41400

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 14828 AN: 20260

East Asian (EAS) AF: 0.901 AC: 31138 AN: 34546

South Asian (SAS) AF: 0.656 AC: 44663 AN: 68032

European-Finnish (FIN) AF: 0.791 AC: 31368 AN: 39662

Middle Eastern (MID) AF: 0.635 AC: 1604 AN: 2524

European-Non Finnish (NFE) AF: 0.749 AC: 260018 AN: 347272

Other (OTH) AF: 0.754 AC: 24101 AN: 31976

GnomAD4 genome AF: 0.747 AC: 113419 AN: 151886 Hom.: 42568 Cov.: 29 AF XY: 0.749 AC XY: 55553 AN XY: 74216

African (AFR) AF: 0.692 AC: 28623 AN: 41382

American (AMR) AF: 0.815 AC: 12451 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2574 AN: 3470

East Asian (EAS) AF: 0.894 AC: 4595 AN: 5138

South Asian (SAS) AF: 0.694 AC: 3341 AN: 4812

European-Finnish (FIN) AF: 0.792 AC: 8356 AN: 10556

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51124 AN: 67944

Other (OTH) AF: 0.728 AC: 1533 AN: 2106

Alfa AF: 0.751 Hom.: 11600

Bravo AF: 0.747

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.33
PhyloP100		-0.91
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: rs11121832; hg19: chr1-11860120;