chr2-63590288-G-T

Variant names:

• chr2-63590288-G-T
• rs6546018
• NM_005917.4:c.3+1242G>T

Variant summary

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

The NM_005917.4(MDH1):​c.3+1242G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 152,170 control chromosomes in the GnomAD database, including 49,746 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 0.80 (49745 hom., cov: 31)
  • Exomes 𝑓: 0.63 (1 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005917.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	NM_005917.4	MANE Select	c.3+1242G>T		intron	N/A	NP_005908.1
	MDH1	NM_001316374.2		c.3+1242G>T		intron	N/A	NP_001303303.1
	MDH1	NM_001199111.2		c.57+904G>T		intron	N/A	NP_001186040.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	ENST00000233114.13	TSL:1 MANE Select	c.3+1242G>T		intron	N/A	ENSP00000233114.8
	MDH1	ENST00000472098.5	TSL:1	n.49+1242G>T		intron	N/A
	MDH1	ENST00000485155.1	TSL:1	n.68+1242G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.803 AC: 122082 AN: 152044 Hom.: 49675 Cov.: 31

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.768

GnomAD4 exome AF: 0.625 AC: 5 AN: 8 Hom.: 1 AF XY: 0.667 AC XY: 4 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 4 AN: 6

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.803 AC: 122216 AN: 152162 Hom.: 49745 Cov.: 31 AF XY: 0.807 AC XY: 60012 AN XY: 74392

African (AFR) AF: 0.922 AC: 38275 AN: 41528

American (AMR) AF: 0.824 AC: 12614 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2759 AN: 3472

East Asian (EAS) AF: 0.982 AC: 5084 AN: 5178

South Asian (SAS) AF: 0.834 AC: 4016 AN: 4818

European-Finnish (FIN) AF: 0.778 AC: 8240 AN: 10586

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48612 AN: 67966

Other (OTH) AF: 0.771 AC: 1626 AN: 2108

Alfa AF: 0.743 Hom.: 8816

Bravo AF: 0.811

Asia WGS AF: 0.903 AC: 3142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.1
DANN	Benign	0.34
PhyloP100		1.6
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: rs6546018; hg19: chr2-63817422;