chr2-149575713-T-C

Variant names:

• chr2-149575713-T-C
• rs1553453961
• NM_015702.3:c.607A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

MMADHC Gene-Disease associations (from GenCC):

• inborn disorder of cobalamin metabolism and transport

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• methylmalonic aciduria and homocystinuria type cblD

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015702.3. 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
	MMADHC	NM_015702.3	MANE Select	c.607A>G	p.Lys203Glu	missense splice_region	Exon 6 of 8	NP_056517.1	Q9H3L0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.607A>G	p.Lys203Glu	missense splice_region	Exon 6 of 8	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.730A>G	p.Lys244Glu	missense splice_region	Exon 7 of 9	ENSP00000604308.1
	MMADHC	ENST00000422782.2	TSL:5	c.607A>G	p.Lys203Glu	missense splice_region	Exon 6 of 9	ENSP00000408331.2	F8WEC0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Methylmalonic aciduria and homocystinuria type cblD (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.94	T
Polyphen		0.46	P
Vest4		0.56
MutPred		0.46		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
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs1553453961; hg19: chr2-150432227;