rs11125979

Variant names:

• chr2-63597172-T-G
• rs11125979
• NM_005917.4:c.200-227T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005917.4(MDH1):​c.200-227T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 570,194 control chromosomes in the GnomAD database, including 18,014 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6258 hom., cov: 32)
  • Exomes 𝑓: 0.24 (11756 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267
• Publications: 3 publications found

Genes affected

MDH1 (HGNC:6970): (malate dehydrogenase 1) This gene encodes an enzyme that catalyzes the NAD/NADH-dependent, reversible oxidation of malate to oxaloacetate in many metabolic pathways, including the citric acid cycle. Two main isozymes are known to exist in eukaryotic cells: one is found in the mitochondrial matrix and the other in the cytoplasm. This gene encodes the cytosolic isozyme, which plays a key role in the malate-aspartate shuttle that allows malate to pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes. Alternatively spliced transcript variants have been found for this gene. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Pseudogenes have been identified on chromosomes X and 6. [provided by RefSeq, Feb 2016]

WDPCP (HGNC:28027): (WD repeat containing planar cell polarity effector) This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WDPCP Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• heart defect - tongue hamartoma - polysyndactyly syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH1	NM_005917.4	c.200-227T>G		intron_variant	Intron 3 of 8	ENST00000233114.13	NP_005908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH1	ENST00000233114.13	c.200-227T>G		intron_variant	Intron 3 of 8	1	NM_005917.4	ENSP00000233114.8

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40325 AN: 151982 Hom.: 6241 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.236 AC: 98505 AN: 418094 Hom.: 11756 AF XY: 0.236 AC XY: 46573 AN XY: 197508

African (AFR) AF: 0.242 AC: 1841 AN: 7592

American (AMR) AF: 0.346 AC: 164 AN: 474

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 509 AN: 2564

East Asian (EAS) AF: 0.723 AC: 1276 AN: 1766

South Asian (SAS) AF: 0.371 AC: 3073 AN: 8284

European-Finnish (FIN) AF: 0.287 AC: 35 AN: 122

Middle Eastern (MID) AF: 0.230 AC: 192 AN: 834

European-Non Finnish (NFE) AF: 0.230 AC: 87926 AN: 382966

Other (OTH) AF: 0.259 AC: 3489 AN: 13492

GnomAD4 genome AF: 0.265 AC: 40382 AN: 152100 Hom.: 6258 Cov.: 32 AF XY: 0.270 AC XY: 20049 AN XY: 74346

African (AFR) AF: 0.241 AC: 9986 AN: 41476

American (AMR) AF: 0.341 AC: 5210 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 759 AN: 3470

East Asian (EAS) AF: 0.710 AC: 3670 AN: 5170

South Asian (SAS) AF: 0.385 AC: 1856 AN: 4824

European-Finnish (FIN) AF: 0.230 AC: 2430 AN: 10582

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15496 AN: 67992

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.235 Hom.: 736

Bravo AF: 0.278

Asia WGS AF: 0.558 AC: 1935 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.0
DANN	Benign	0.63
PhyloP100		-0.27
Mutation Taster		=100/0	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: rs11125979; hg19: chr2-63824306;