rs758206023

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_005957.5(MTHFR):​c.1808C>T​(p.Ser603Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S603C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

8
10
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.45

Publications

3 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-11790843-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 187904.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTHFRNM_005957.5 linkc.1808C>T p.Ser603Phe missense_variant Exon 12 of 12 ENST00000376590.9 NP_005948.3 P42898-1Q8IU67Q59GJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTHFRENST00000376590.9 linkc.1808C>T p.Ser603Phe missense_variant Exon 12 of 12 1 NM_005957.5 ENSP00000365775.3 P42898-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251452
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;D;.;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.96
.;D;.;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Pathogenic
3.8
H;.;.;H;.;.
PhyloP100
9.4
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.5
D;D;D;D;.;.
REVEL
Uncertain
0.58
Sift
Uncertain
0.0010
D;D;D;D;.;.
Sift4G
Uncertain
0.0020
D;D;D;D;.;.
Polyphen
1.0
D;.;.;D;.;.
Vest4
0.70
MutPred
0.34
Loss of disorder (P = 3e-04);.;.;Loss of disorder (P = 3e-04);.;.;
MVP
0.88
MPC
0.95
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.75
gMVP
0.97
Mutation Taster
=6/94
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs758206023; hg19: chr1-11850900; API