1-11790692-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005957.5(MTHFR):​c.1959G>A​(p.Thr653=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,614,138 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 4 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 synonymous

Scores

6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.67
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0048999786).
BP6
Variant 1-11790692-C-T is Benign according to our data. Variant chr1-11790692-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 498489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.67 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00186 (283/152280) while in subpopulation AFR AF= 0.00657 (273/41550). AF 95% confidence interval is 0.00593. There are 4 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTHFRNM_005957.5 linkuse as main transcriptc.1959G>A p.Thr653= synonymous_variant 12/12 ENST00000376590.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFRENST00000376590.9 linkuse as main transcriptc.1959G>A p.Thr653= synonymous_variant 12/121 NM_005957.5 A1P42898-1

Frequencies

GnomAD3 genomes
AF:
0.00183
AC:
278
AN:
152162
Hom.:
4
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00647
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000474
AC:
119
AN:
251294
Hom.:
1
AF XY:
0.000361
AC XY:
49
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.00671
Gnomad AMR exome
AF:
0.0000868
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:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000244
AC:
356
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.000223
AC XY:
162
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00759
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.000629
GnomAD4 genome
AF:
0.00186
AC:
283
AN:
152280
Hom.:
4
Cov.:
33
AF XY:
0.00161
AC XY:
120
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00657
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000998
Hom.:
0
Bravo
AF:
0.00199
ESP6500AA
AF:
0.00477
AC:
21
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000576
AC:
70
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000296

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 03, 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. -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2023MTHFR: BS2 -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 27, 2016- -
Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 05, 2021- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 21, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.024
DANN
Benign
0.61
FATHMM_MKL
Benign
0.0027
N
LIST_S2
Benign
0.35
T
MetaRNN
Benign
0.0049
T
MutationTaster
Benign
1.0
N;N;N;N
GERP RS
-10

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.

Other links and lift over

dbSNP: rs45572531; hg19: chr1-11850749; COSMIC: COSV100453372; COSMIC: COSV100453372; API