rs11545261

Positions:

• chr2-149576462-C-A
• chr2-149576462-C-G
• chr2-149576462-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015702.3(MMADHC):​c.453G>T​(p.Gln151His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q151Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMADHC NM_015702.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920

Genes affected

MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.453G>T	p.Gln151His	missense_variant	5/8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.453G>T	p.Gln151His	missense_variant	5/8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.453G>T	p.Gln151His	missense_variant	5/9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.453G>T	p.Gln151His	missense_variant	4/7	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;D
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D;D;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.68
MutPred		0.68		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.81
MPC		0.13
ClinPred		0.97	D
GERP RS		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.57

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: rs11545261; hg19: chr2-150432976;