rs11538800

Variant names:

• chr7-76048176-G-C
• rs11538800
• NM_005918.4:c.16G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-76048176-G-C
• chr7-76048176-G-A
• chr7-76048176-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005918.4(MDH2):​c.16G>C​(p.Ala6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,384,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MDH2 NM_005918.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.77
• Publications: 0 publications found

Genes affected

MDH2 (HGNC:6971): (malate dehydrogenase 2) Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

STYXL1 (HGNC:18165): (serine/threonine/tyrosine interacting like 1) Enables protein phosphatase binding activity; protein phosphatase inhibitor activity; and pseudophosphatase activity. Involved in several processes, including negative regulation of phosphoprotein phosphatase activity; negative regulation of stress granule assembly; and positive regulation of intrinsic apoptotic signaling pathway. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26725328).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005918.4. 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
	MDH2	NM_005918.4	MANE Select	c.16G>C	p.Ala6Pro	missense	Exon 1 of 9	NP_005909.2
	MDH2	NM_001282403.2		c.16G>C	p.Ala6Pro	missense	Exon 1 of 8	NP_001269332.1	P40926-2
	MDH2	NM_001282404.2		c.-137G>C		5_prime_UTR	Exon 1 of 8	NP_001269333.1	G3XAL0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH2	ENST00000315758.10	TSL:1 MANE Select	c.16G>C	p.Ala6Pro	missense	Exon 1 of 9	ENSP00000327070.5	P40926-1
	MDH2	ENST00000971443.1		c.16G>C	p.Ala6Pro	missense	Exon 1 of 9	ENSP00000641502.1
	MDH2	ENST00000854579.1		c.16G>C	p.Ala6Pro	missense	Exon 1 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384174 Hom.: 0 Cov.: 51 AF XY: 0.00000146 AC XY: 1 AN XY: 683308

African (AFR) AF: 0.00 AC: 0 AN: 31556

American (AMR) AF: 0.00 AC: 0 AN: 35972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078580

Other (OTH) AF: 0.00 AC: 0 AN: 57842

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.024
Eigen_PC	Benign	0.093
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.085	T
Sift4G	Benign	0.19	T
Polyphen		0.45	B
Vest4		0.42
MutPred		0.27		Loss of MoRF binding (P = 0.0157)
MVP		0.71
MPC		0.23
ClinPred		0.96	D
GERP RS		3.7
PromoterAI		0.014	Neutral
Varity_R		0.46
gMVP		0.61
Mutation Taster		=69/31	polymorphism

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: rs11538800; hg19: chr7-75677494;