5-78998233-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013391.3(DMGDH):​c.2450A>T​(p.Tyr817Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DMGDH
NM_013391.3 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
Variant links:
Genes affected
DMGDH (HGNC:24475): (dimethylglycine dehydrogenase) This gene encodes an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine to form sarcosine. The enzyme is found as a monomer in the mitochondrial matrix, and uses flavin adenine dinucleotide and folate as cofactors. Mutation in this gene causes dimethylglycine dehydrogenase deficiency, characterized by a fishlike body odor, chronic muscle fatigue, and elevated levels of the muscle form of creatine kinase in serum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DMGDHNM_013391.3 linkuse as main transcriptc.2450A>T p.Tyr817Phe missense_variant 16/16 ENST00000255189.8 NP_037523.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DMGDHENST00000255189.8 linkuse as main transcriptc.2450A>T p.Tyr817Phe missense_variant 16/161 NM_013391.3 ENSP00000255189 P1Q9UI17-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251444
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135898
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 07, 2023The c.2450A>T (p.Y817F) alteration is located in exon 16 (coding exon 16) of the DMGDH gene. This alteration results from a A to T substitution at nucleotide position 2450, causing the tyrosine (Y) at amino acid position 817 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
0.0026
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T
Eigen
Benign
0.12
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.65
D
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.43
Sift
Uncertain
0.018
D
Sift4G
Benign
0.064
T
Polyphen
0.37
B
Vest4
0.64
MutPred
0.68
Loss of catalytic residue at Y817 (P = 0.0949);
MVP
0.71
MPC
0.59
ClinPred
0.75
D
GERP RS
6.2
Varity_R
0.55
gMVP
0.65

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: rs762005988; hg19: chr5-78294056; API