Variant 1-11790681-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5

The NM_005957.5(MTHFR):c.1970G>C(p.Ter657SerextTer50) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,786 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 stop_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 0.559

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in NM_005957.5 Downstream stopcodon found after 72 codons.

PP5

Variant 1-11790681-C-G is Pathogenic according to our data. Variant chr1-11790681-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 975602.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.1970G>C	p.Ter657SerextTer50	stop_lost	12/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.1970G>C	p.Ter657SerextTer50	stop_lost	12/12	1	NM_005957.5	ENSP00000365775	A1	P42898-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251184

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135770

show subpopulations

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727174

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2023	Variant summary: MTHFR c.1970G>C (p.X657SerextX50) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. MTHFR c.1970G>C (p.X657SerextX50) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 1.2e-05 in 251184 control chromosomes. c.1970G>C has been reported in the homozygous state in brothers with severe methylenetetrahydrofolate reductase deficiency (Tonetti_2003) as well as in a an affected patient with unclassified second allele who had <2% residual MTHFR activity in fibroblasts (Huemer_2016). These data indicate that the variant is likely to be associated with disease. While this variant has not been experimentally tested, a different variant resulting in a similar protein extension (p.657Argextfs50) has been reported experimentally to lead to <2% MTHFR activity (Burda_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25736335, 26025547, 12733064). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2022	This sequence change disrupts the translational stop signal of the MTHFR mRNA. It is expected to extend the length of the MTHFR protein by 50 additional amino acid residues. This variant is present in population databases (rs749490263, gnomAD 0.003%). This protein extension has been observed in individual(s) with severe methylenetetrahydrofolate reductase deficiency (PMID: 12733064). ClinVar contains an entry for this variant (Variation ID: 975602). This variant disrupts the C-terminus of the MTHFR protein. Other variant(s) that disrupt this region (c.1969T>C (p.657Serext50)) have been observed in individuals with MTHFR-related conditions (PMID: 25736335). This suggests that this may be a clinically significant region of the protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neural tube defects, folate-sensitive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2024

- -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.5

DANN

Benign

0.77

Eigen

Uncertain

0.29

Eigen_PC

Benign

-0.057

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.26

MetaRNN

Benign

0.30

MutationTaster

Benign

1.0

N;N;N;N

GERP RS

3.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over