NM_005917.4:c.3+346A>G

Variant names:

• chr2-63589392-A-G
• rs201758772
• NM_005917.4:c.3+346A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005917.4(MDH1):​c.3+346A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,550,354 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (1 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Scores: Splicing: ADA: 0.00006381
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.475
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Variant has high frequency in the NFE (0.00296) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 1).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-63589392-A-G is Benign according to our data. Variant chr2-63589392-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3067236.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	NM_005917.4	MANE Select	c.3+346A>G		intron	N/A	NP_005908.1	P40925-1
	MDH1	NM_001316374.2		c.3+346A>G		intron	N/A	NP_001303303.1	A0A5K1VW95
	MDH1	NM_001199111.2		c.57+8A>G		splice_region intron	N/A	NP_001186040.1	P40925-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	ENST00000233114.13	TSL:1 MANE Select	c.3+346A>G		intron	N/A	ENSP00000233114.8	P40925-1
	MDH1	ENST00000472098.5	TSL:1	n.49+346A>G		intron	N/A
	MDH1	ENST00000485155.1	TSL:1	n.68+346A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00123 AC: 184 AN: 149358 AF XY: 0.00121

Gnomad AFR exome AF: 0.000296

Gnomad AMR exome AF: 0.000976

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.000927

GnomAD4 exome AF: 0.00258 AC: 3601 AN: 1398048 Hom.: 1 Cov.: 31 AF XY: 0.00249 AC XY: 1717 AN XY: 689562

African (AFR) AF: 0.000506 AC: 16 AN: 31594

American (AMR) AF: 0.00165 AC: 59 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.000644 AC: 51 AN: 79232

European-Finnish (FIN) AF: 0.000997 AC: 48 AN: 48164

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.00304 AC: 3282 AN: 1078760

Other (OTH) AF: 0.00245 AC: 142 AN: 57988

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00153 AC XY: 114 AN XY: 74472

African (AFR) AF: 0.000577 AC: 24 AN: 41572

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00246 AC: 167 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.8
DANN	Benign	0.55
PhyloP100		-0.47
PromoterAI		0.081	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.010
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: rs201758772; hg19: chr2-63816526;