1-11794732-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_005957.5(MTHFR):c.1163G>A(p.Arg388His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R388C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.39

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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 1-11794732-C-T is Pathogenic according to our data. Variant chr1-11794732-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548463.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.1163G>A	p.Arg388His	missense_variant	Exon 7 of 12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.1163G>A	p.Arg388His	missense_variant	Exon 7 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251490

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135922

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

May 01, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MTHFR c.1163G>A (p.Arg388His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251490 control chromosomes. c.1163G>A has been reported in the literature at a compound heterozygous state with a second VUS missense in one individual affected with unspecified genetic disease (Capalbo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Weile_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 34214447). ClinVar contains an entry for this variant (Variation ID: 548463). Based on the evidence outlined above, the variant was classified as VUS. -

not provided

Uncertain:1

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

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

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

4.1

H;.;.;H;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.9

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

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.92

MutPred

0.75

Gain of catalytic residue at R388 (P = 0.0874);.;.;Gain of catalytic residue at R388 (P = 0.0874);.;Gain of catalytic residue at R388 (P = 0.0874);.;

MVP

0.96

MPC

1.0

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.92

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