rs786204033

Variant names:

• chr1-11790916-C-T
• rs777661576
• NM_005957.5:c.1753-18G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_005957.5(MTHFR):​c.1753-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,602,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.339

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-11790916-C-T is Pathogenic according to our data. Variant chr1-11790916-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 187901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1753-18G>A		intron_variant	Intron 11 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1753-18G>A		intron_variant	Intron 11 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250046 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1450742 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3 AN XY: 722244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2

-

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with MTHFR deficiency (PMID: 25736335). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 25736335). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 187901). This variant is also known as c.1765-18G>A. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 11 of the MTHFR gene. It does not directly change the encoded amino acid sequence of the MTHFR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

Neural tube defects, folate-sensitive Pathogenic:1

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	18
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: -2
DS_AL_spliceai		0.58		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs777661576; hg19: chr1-11850973;