chr2-63603735-G-A

Variant names:

• chr2-63603735-G-A
• rs262471
• NM_005917.4:c.499-961G>A

Variant summary

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

The NM_005917.4(MDH1):​c.499-961G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 149,326 control chromosomes in the GnomAD database, including 48,844 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 (48844 hom., cov: 23)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.661
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH1	NM_005917.4	c.499-961G>A		intron_variant	Intron 5 of 8	ENST00000233114.13	NP_005908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH1	ENST00000233114.13	c.499-961G>A		intron_variant	Intron 5 of 8	1	NM_005917.4	ENSP00000233114.8

Frequencies

GnomAD3 genomes AF: 0.804 AC: 120007 AN: 149216 Hom.: 48779 Cov.: 23

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.773

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.804 AC: 120131 AN: 149326 Hom.: 48844 Cov.: 23 AF XY: 0.809 AC XY: 58754 AN XY: 72666

African (AFR) AF: 0.922 AC: 37436 AN: 40598

American (AMR) AF: 0.829 AC: 12393 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2751 AN: 3460

East Asian (EAS) AF: 0.982 AC: 4959 AN: 5052

South Asian (SAS) AF: 0.835 AC: 3916 AN: 4690

European-Finnish (FIN) AF: 0.788 AC: 7811 AN: 9916

Middle Eastern (MID) AF: 0.773 AC: 221 AN: 286

European-Non Finnish (NFE) AF: 0.716 AC: 48303 AN: 67432

Other (OTH) AF: 0.776 AC: 1582 AN: 2038

Alfa AF: 0.741 Hom.: 4364

Bravo AF: 0.810

Asia WGS AF: 0.902 AC: 3138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.53
DANN	Benign	0.61
PhyloP100		-0.66
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: rs262471; hg19: chr2-63830869;