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GeneBe

1-11790693-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005957(MTHFR):c.1958C>T(p.Thr653Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 152192 control chromosomes in the gnomAD Genomes database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (β˜…β˜…). Synonymous variant affecting the same amino acid position (i.e. T653T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)
Exomes 𝑓: 0.014 ( 29 hom. )

Consequence

MTHFR
NM_005957 missense

Scores

17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.301

Links

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
?
Computational evidence support a benign effect (MetaRNN=0.003030628).
BP6
?
Variant 1:11790693-G>A is Benign according to our data. Variant chr1-11790693-G-A is described in ClinVar as [Benign]. Clinvar id is 281891. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11790693-G-A is described in Lovd as [Benign]. Variant chr1-11790693-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected. gnomad allele frequency = 0.0141 (2146/152192) while in subpopulation NFE AF= 0.022 (1497/68028). AF 95% confidence interval is 0.0211. There are 24 homozygotes in gnomad. There are 987 alleles in male gnomad subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTHFRNM_005957.5 linkuse as main transcriptc.1958C>T p.Thr653Met missense_variant 12/12 ENST00000376590.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFRENST00000376590.9 linkuse as main transcriptc.1958C>T p.Thr653Met missense_variant 12/121 NM_005957.5 A1P42898-1

Frequencies

GnomAD3 genomes
AF:
0.0141
AC:
2146
AN:
152192
Hom.:
24
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00398
Gnomad AMI
AF:
0.0252
Gnomad AMR
AF:
0.0154
Gnomad ASJ
AF:
0.0213
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00951
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0220
Gnomad OTH
AF:
0.0167
GnomAD3 exomes
AF:
0.0137
AC:
3432
AN:
251292
Hom.:
29
AF XY:
0.0137
AC XY:
1865
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00357
Gnomad AMR exome
AF:
0.00935
Gnomad ASJ exome
AF:
0.0207
Gnomad EAS exome
AF:
0.000218
Gnomad SAS exome
AF:
0.00304
Gnomad FIN exome
AF:
0.00957
Gnomad NFE exome
AF:
0.0216
Gnomad OTH exome
AF:
0.0145
GnomAD4 exome
AF:
0.0194
AC:
28383
AN:
1461852
Hom.:
323
AF XY:
0.0191
AC XY:
13902
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00344
Gnomad4 AMR exome
AF:
0.0100
Gnomad4 ASJ exome
AF:
0.0204
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00307
Gnomad4 FIN exome
AF:
0.0100
Gnomad4 NFE exome
AF:
0.0229
Gnomad4 OTH exome
AF:
0.0160
Alfa
AF:
0.0211
Hom.:
63
Bravo
AF:
0.0144
TwinsUK
AF:
0.0205
AC:
76
ALSPAC
AF:
0.0244
AC:
94
ESP6500AA
AF:
0.00272
AC:
12
ESP6500EA
AF:
0.0265
AC:
228
ExAC
AF:
0.0138
AC:
1681
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.0202
EpiControl
AF:
0.0234

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 13, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 17, 2020- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 16, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeNov 02, 2022- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.53
Cadd
Benign
0.85
Dann
Benign
0.90
DEOGEN2
Benign
0.17
T;.;.;T;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.033
N
MetaRNN
Benign
0.0030
T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.69
N;.;.;N;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.45
N;N;N;N;.;.
REVEL
Benign
0.14
Sift
Benign
0.16
T;T;T;T;.;.
Sift4G
Benign
0.096
T;T;T;T;.;.
Polyphen
0.0020
B;.;.;B;.;.
Vest4
0.037
MPC
0.27
ClinPred
0.0013
T
GERP RS
-3.5
Varity_R
0.016
gMVP
0.21

Splicing

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs35737219; hg19: chr1-11850750; COSMIC: COSV99060080; COSMIC: COSV99060080;