rs4671069

Variant names:

• chr2-63598270-C-A
• rs4671069
• NM_005917.4:c.375+696C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-63598270-C-A
• chr2-63598270-C-G
• chr2-63598270-C-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.375+696C>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 152,150 control chromosomes in the GnomAD database, including 49,839 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 (49788 hom., cov: 29)
  • Exomes 𝑓: 0.74 (51 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• 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=-1.01).
• 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.375+696C>A		intron_variant	Intron 4 of 8	ENST00000233114.13	NP_005908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH1	ENST00000233114.13	c.375+696C>A		intron_variant	Intron 4 of 8	1	NM_005917.4	ENSP00000233114.8

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122048 AN: 151846 Hom.: 49718 Cov.: 29

Gnomad AFR AF: 0.924

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: 0.779

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.768

GnomAD4 exome AF: 0.737 AC: 137 AN: 186 Hom.: 51 AF XY: 0.747 AC XY: 112 AN XY: 150

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.833 AC: 5 AN: 6

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 6 AN: 6

East Asian (EAS) AF: 1.00 AC: 4 AN: 4

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.720 AC: 118 AN: 164

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.804 AC: 122182 AN: 151964 Hom.: 49788 Cov.: 29 AF XY: 0.807 AC XY: 59973 AN XY: 74278

African (AFR) AF: 0.924 AC: 38315 AN: 41458

American (AMR) AF: 0.825 AC: 12580 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2756 AN: 3468

East Asian (EAS) AF: 0.982 AC: 5087 AN: 5182

South Asian (SAS) AF: 0.834 AC: 4010 AN: 4806

European-Finnish (FIN) AF: 0.779 AC: 8212 AN: 10546

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

European-Non Finnish (NFE) AF: 0.716 AC: 48613 AN: 67942

Other (OTH) AF: 0.771 AC: 1619 AN: 2100

Alfa AF: 0.687 Hom.: 2476

Bravo AF: 0.811

Asia WGS AF: 0.904 AC: 3143 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	0.87
DANN	Benign	0.56
PhyloP100		-1.2
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: rs4671069; hg19: chr2-63825404;