5-79044463-A-G

Variant names:

• chr5-79044463-A-G
• rs532964
• NM_013391.3:c.835T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013391.3(DMGDH):​c.835T>C​(p.Ser279Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,386 control chromosomes in the GnomAD database, including 235,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24034 hom., cov: 33)
  • Exomes 𝑓: 0.54 (211515 hom.)
• Consequence: DMGDH NM_013391.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.96
• Publications: 40 publications found

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]

DMGDH Gene-Disease associations (from GenCC):

• dimethylglycine dehydrogenase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2679009E-6).
• BP6: Variant 5-79044463-A-G is Benign according to our data. Variant chr5-79044463-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMGDH	NM_013391.3	c.835T>C	p.Ser279Pro	missense_variant	Exon 6 of 16	ENST00000255189.8	NP_037523.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMGDH	ENST00000255189.8	c.835T>C	p.Ser279Pro	missense_variant	Exon 6 of 16	1	NM_013391.3	ENSP00000255189.3

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84951 AN: 151970 Hom.: 24003 Cov.: 33

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.560

GnomAD2 exomes AF: 0.559 AC: 140606 AN: 251334 AF XY: 0.558

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.581

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.781

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.530

GnomAD4 exome AF: 0.535 AC: 782218 AN: 1461298 Hom.: 211515 Cov.: 51 AF XY: 0.536 AC XY: 389412 AN XY: 726978

African (AFR) AF: 0.593 AC: 19852 AN: 33464

American (AMR) AF: 0.574 AC: 25657 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12441 AN: 26132

East Asian (EAS) AF: 0.765 AC: 30368 AN: 39698

South Asian (SAS) AF: 0.569 AC: 49078 AN: 86246

European-Finnish (FIN) AF: 0.528 AC: 28209 AN: 53398

Middle Eastern (MID) AF: 0.548 AC: 3158 AN: 5768

European-Non Finnish (NFE) AF: 0.522 AC: 580034 AN: 1111508

Other (OTH) AF: 0.554 AC: 33421 AN: 60376

GnomAD4 genome AF: 0.559 AC: 85033 AN: 152088 Hom.: 24034 Cov.: 33 AF XY: 0.559 AC XY: 41549 AN XY: 74336

African (AFR) AF: 0.598 AC: 24799 AN: 41478

American (AMR) AF: 0.579 AC: 8858 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1686 AN: 3468

East Asian (EAS) AF: 0.779 AC: 4030 AN: 5172

South Asian (SAS) AF: 0.570 AC: 2743 AN: 4816

European-Finnish (FIN) AF: 0.532 AC: 5623 AN: 10562

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35299 AN: 67988

Other (OTH) AF: 0.563 AC: 1187 AN: 2110

Alfa AF: 0.536 Hom.: 59160

Bravo AF: 0.566

TwinsUK AF: 0.529 AC: 1961

ALSPAC AF: 0.514 AC: 1982

ESP6500AA AF: 0.601 AC: 2648

ESP6500EA AF: 0.526 AC: 4526

ExAC AF: 0.561 AC: 68148

Asia WGS AF: 0.696 AC: 2421 AN: 3478

EpiCase AF: 0.522

EpiControl AF: 0.523

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.27
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.7	N;.
PhyloP100		8.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	5.9	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.054
ClinPred		0.012	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.55
Mutation Taster		=66/34	polymorphism (auto)

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

Other links and lift over

dbSNP: rs532964; hg19: chr5-78340286; COSMIC: COSV54862098;