rs2066471

Variant names:

• chr1-11800401-C-G
• rs2066471
• NM_005957.5:c.476-79G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-11800401-C-G
• chr1-11800401-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005957.5(MTHFR):​c.476-79G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,065,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• Publications: 22 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.476-79G>C		intron_variant	Intron 3 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.476-79G>C		intron_variant	Intron 3 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 11 AN: 913596 Hom.: 0 Cov.: 13 AF XY: 0.00000628 AC XY: 3 AN XY: 477706

African (AFR) AF: 0.000439 AC: 10 AN: 22774

American (AMR) AF: 0.00 AC: 0 AN: 43404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22590

East Asian (EAS) AF: 0.00 AC: 0 AN: 37062

South Asian (SAS) AF: 0.00 AC: 0 AN: 75096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 614124

Other (OTH) AF: 0.0000236 AC: 1 AN: 42316

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74274

African (AFR) AF: 0.000459 AC: 19 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 791

Bravo AF: 0.000128

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.2
DANN	Benign	0.53
PhyloP100		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2066471; hg19: chr1-11860458;