rs17375901

Variant names:

• chr1-11792459-C-T
• rs17375901
• NM_005957.5:c.1531-80G>A

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.1531-80G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 996,390 control chromosomes in the GnomAD database, including 1,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (209 hom., cov: 33)
  • Exomes 𝑓: 0.050 (1273 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.144
• Publications: 39 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=-0.83).
• BP6: Variant 1-11792459-C-T is Benign according to our data. Variant chr1-11792459-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1531-80G>A		intron_variant	Intron 9 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1531-80G>A		intron_variant	Intron 9 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6961 AN: 152216 Hom.: 209 Cov.: 33

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0430

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0579

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.0495 AC: 41801 AN: 844056 Hom.: 1273 AF XY: 0.0497 AC XY: 22066 AN XY: 444250

African (AFR) AF: 0.0280 AC: 606 AN: 21630

American (AMR) AF: 0.0192 AC: 816 AN: 42496

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 341 AN: 22292

East Asian (EAS) AF: 0.000136 AC: 5 AN: 36676

South Asian (SAS) AF: 0.0446 AC: 3277 AN: 73454

European-Finnish (FIN) AF: 0.0945 AC: 3982 AN: 42130

Middle Eastern (MID) AF: 0.0273 AC: 103 AN: 3772

European-Non Finnish (NFE) AF: 0.0550 AC: 30873 AN: 561296

Other (OTH) AF: 0.0446 AC: 1798 AN: 40310

GnomAD4 genome AF: 0.0457 AC: 6961 AN: 152334 Hom.: 209 Cov.: 33 AF XY: 0.0475 AC XY: 3539 AN XY: 74480

African (AFR) AF: 0.0272 AC: 1133 AN: 41586

American (AMR) AF: 0.0212 AC: 324 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0426 AC: 206 AN: 4832

European-Finnish (FIN) AF: 0.113 AC: 1193 AN: 10602

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0579 AC: 3939 AN: 68036

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0530 Hom.: 223

Bravo AF: 0.0375

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.64
DANN	Benign	0.70
PhyloP100		0.14
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: rs17375901; hg19: chr1-11852516;