chr2-206751066-T-C

Position:

• chr2-206751066-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039845.3(MDH1B):​c.920A>G​(p.Asp307Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,420,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MDH1B NM_001039845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13

Genes affected

MDH1B (HGNC:17836): (malate dehydrogenase 1B) Predicted to enable L-malate dehydrogenase activity. Predicted to be involved in NADH metabolic process; dicarboxylic acid metabolic process; and tricarboxylic acid cycle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDH1B	NM_001039845.3	c.920A>G	p.Asp307Gly	missense_variant	6/12	ENST00000374412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDH1B	ENST00000374412.8	c.920A>G	p.Asp307Gly	missense_variant	6/12	1	NM_001039845.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000845 AC: 2 AN: 236680 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127938

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1420744 Hom.: 0 Cov.: 27 AF XY: 0.00000142 AC XY: 1 AN XY: 705696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000494

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.920A>G (p.D307G) alteration is located in exon 6 (coding exon 6) of the MDH1B gene. This alteration results from a A to G substitution at nucleotide position 920, causing the aspartic acid (D) at amino acid position 307 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.79	P;.;P
Vest4		0.68
MutPred		0.54		Gain of MoRF binding (P = 0.0311);.;Gain of MoRF binding (P = 0.0311);
MVP		0.73
MPC		0.51
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.41
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs748486686; hg19: chr2-207615790;