rs1553453961

Positions:

• chr2-149575713-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015702.3(MMADHC):​c.607A>G​(p.Lys203Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMADHC NM_015702.3 missense, splice_region
• Scores: Splicing: ADA: 0.1273
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

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.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity MMAD_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.607A>G	p.Lys203Glu	missense_variant, splice_region_variant	6/8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.607A>G	p.Lys203Glu	missense_variant, splice_region_variant	6/8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.607A>G	p.Lys203Glu	missense_variant, splice_region_variant	6/9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.607A>G	p.Lys203Glu	missense_variant, splice_region_variant	5/7	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T;T;D
Sift4G	Benign	0.94	T;T;T
Polyphen		0.46	P;P;B
Vest4		0.56
MutPred		0.46		Loss of ubiquitination at K203 (P = 0.013);Loss of ubiquitination at K203 (P = 0.013);Loss of ubiquitination at K203 (P = 0.013);
MVP		0.81
MPC		0.082
ClinPred		0.92	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.35
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: rs1553453961; hg19: chr2-150432227;