chr1-11795125-C-T

Position:

chr1-11795125-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP5BP4

The NM_005957.5(MTHFR):c.1004G>A(p.Arg335His) variant causes a missense change. The variant allele was found at a frequency of 0.0000366 in 1,613,074 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 3.63

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:

MTHFR (HGNC:):

MTHFR links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_005957.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11795126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2054912.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

PP5

Variant 1-11795125-C-T is Pathogenic according to our data. Variant chr1-11795125-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187886.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.3067227). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	6/12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.1004G>A	p.Arg335His	missense_variant	6/12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000480

AC:

AN:

249888

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1460730

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 335 of the MTHFR protein (p.Arg335His). 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 missense change has been observed in individual(s) with clinical features of severe methylenetetrahydrofolate reductase deficiency (PMID: 25736335, 34015165; Invitae). This variant is also known as c.1016G>A. ClinVar contains an entry for this variant (Variation ID: 187886). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTHFR protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MTHFR function (PMID: 27743313). This variant disrupts the p.Arg335 amino acid residue in MTHFR. Other variant(s) that disrupt this residue have been observed in individuals with MTHFR-related conditions (PMID: 7726158), which suggests that this may be a clinically significant amino acid residue. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	May 13, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	University Children's Hospital, University of Zurich	-	- -

Neural tube defects, folate-sensitive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 21, 2024

Variant summary: MTHFR c.1004G>A (p.Arg335His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249888 control chromosomes (gnomAD). c.1004G>A has been reported in the literature in individuals affected with clinical features of severe methylene tetrahydrofolate reductase deficiency (examples: Zhai_2021, Burda_2017). These data do not allow any conclusion about variant significance. A different variant that disrupts this residue has been classified pathogenic internally, which suggests that this may be a clinically significant amino acid residue. Experimental studies have evaluated the variant effect in vitro however, the data is inconclusive (example: Weile_2021, Burda_2017). The following publications have been ascertained in the context of this evaluation (PMID: 34015165, 34214447, 27743313, 25736335). ClinVar contains an entry for this variant (Variation ID: 187886). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.;.;D;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

.;D;.;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.31

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.6

M;.;.;M;.;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.68

N;N;N;N;.;.;.

REVEL

Uncertain

0.57

Sift

Benign

0.13

T;D;D;T;.;.;.

Sift4G

Benign

0.11

T;T;T;T;.;.;.

Polyphen

0.79

P;.;.;P;.;.;.

Vest4

0.26

MutPred

0.61

Loss of MoRF binding (P = 0.0372);.;.;Loss of MoRF binding (P = 0.0372);.;Loss of MoRF binding (P = 0.0372);.;

MVP

0.98

MPC

0.77

ClinPred

0.26

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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