rs7533315

Variant names:

• chr1-11800626-T-C
• rs7533315
• NM_005957.5:c.476-304A>G

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.476-304A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 454,420 control chromosomes in the GnomAD database, including 127,735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42583 hom., cov: 30)
  • Exomes 𝑓: 0.75 (85152 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.348
• Publications: 19 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=-0.86).
• BP6: Variant 1-11800626-T-C is Benign according to our data. Variant chr1-11800626-T-C is described in ClinVar as Benign. ClinVar VariationId is 1249614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.874 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.476-304A>G		intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.599-304A>G		intron	N/A	NP_001317287.1
	MTHFR	NM_001410750.1		c.596-304A>G		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.476-304A>G		intron	N/A	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.596-304A>G		intron	N/A	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.476-304A>G		intron	N/A	ENSP00000365777.1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113368 AN: 151808 Hom.: 42553 Cov.: 30

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.895

Gnomad SAS AF: 0.695

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.747 AC: 226056 AN: 302494 Hom.: 85152 Cov.: 0 AF XY: 0.739 AC XY: 119629 AN XY: 161944

African (AFR) AF: 0.690 AC: 5994 AN: 8688

American (AMR) AF: 0.841 AC: 11722 AN: 13944

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 6348 AN: 8608

East Asian (EAS) AF: 0.898 AC: 14923 AN: 16620

South Asian (SAS) AF: 0.657 AC: 28331 AN: 43110

European-Finnish (FIN) AF: 0.792 AC: 13156 AN: 16612

Middle Eastern (MID) AF: 0.631 AC: 802 AN: 1270

European-Non Finnish (NFE) AF: 0.748 AC: 132565 AN: 177266

Other (OTH) AF: 0.746 AC: 12215 AN: 16376

GnomAD4 genome AF: 0.747 AC: 113456 AN: 151926 Hom.: 42583 Cov.: 30 AF XY: 0.749 AC XY: 55601 AN XY: 74270

African (AFR) AF: 0.692 AC: 28646 AN: 41384

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

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2573 AN: 3468

East Asian (EAS) AF: 0.895 AC: 4615 AN: 5156

South Asian (SAS) AF: 0.694 AC: 3335 AN: 4808

European-Finnish (FIN) AF: 0.791 AC: 8363 AN: 10568

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

European-Non Finnish (NFE) AF: 0.752 AC: 51120 AN: 67960

Other (OTH) AF: 0.728 AC: 1535 AN: 2108

Alfa AF: 0.756 Hom.: 16888

Bravo AF: 0.747

Asia WGS AF: 0.789 AC: 2745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: 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	-0.86
CADD	Benign	0.38
DANN	Benign	0.34
PhyloP100		-0.35
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: rs7533315; hg19: chr1-11860683;