rs2278718

Positions:

• chr2-63588667-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000544381.4(MDH1):​c.-377A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 468,776 control chromosomes in the GnomAD database, including 11,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3713 hom., cov: 32)
  • Exomes 𝑓: 0.21 (8191 hom.)
• Consequence: MDH1 ENST00000544381.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0360

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-63588667-A-C is Benign according to our data. Variant chr2-63588667-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 336779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDPCP	XM_047444626.1	c.-249-17041T>G		intron_variant			XP_047300582.1
WDPCP	XM_047444627.1	c.-249-17041T>G		intron_variant			XP_047300583.1
WDPCP	XM_047444628.1	c.-249-17041T>G		intron_variant			XP_047300584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDPCP	ENST00000431065.1	c.-396T>G		5_prime_UTR_variant	1/4	4		ENSP00000396226
MDH1	ENST00000544381.4	c.-377A>C		5_prime_UTR_variant	1/9	2		ENSP00000446395	P1
MDH1	ENST00000485781.5	n.59A>C		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29612 AN: 151792 Hom.: 3710 Cov.: 32

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.211 AC: 66813 AN: 316866 Hom.: 8191 Cov.: 0 AF XY: 0.204 AC XY: 34252 AN XY: 167708

Gnomad4 AFR exome AF: 0.0504

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.237

Gnomad4 OTH exome AF: 0.194

GnomAD4 genome AF: 0.195 AC: 29625 AN: 151910 Hom.: 3713 Cov.: 32 AF XY: 0.199 AC XY: 14761 AN XY: 74222

Gnomad4 AFR AF: 0.0583

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.172

Alfa AF: 0.230 Hom.: 7152

Bravo AF: 0.177

Asia WGS AF: 0.122 AC: 426 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Bardet-Biedl syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.51

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

Other links and lift over

dbSNP: rs2278718; hg19: chr2-63815801;