rs104893849

chr4-145646043-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_172250.3(MMAA):c.620A>G(p.Tyr207Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMAA NM_172250.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.25

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 4-145646043-A-G is Pathogenic according to our data. Variant chr4-145646043-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3159.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAA	NM_172250.3	c.620A>G	p.Tyr207Cys	missense_variant	4/7	ENST00000649156.2
MMAA	NM_001375644.1	c.620A>G	p.Tyr207Cys	missense_variant	4/7
MMAA	XM_011531684.4	c.620A>G	p.Tyr207Cys	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.620A>G	p.Tyr207Cys	missense_variant	4/7		NM_172250.3	P1
	ENST00000504555.1	n.254-3216T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 26, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.;M;M;M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.81	D
Polyphen		1.0	D;.;D;D;D;.
Vest4		0.94, 0.95
MutPred		0.95		Loss of phosphorylation at Y207 (P = 0.062);Loss of phosphorylation at Y207 (P = 0.062);Loss of phosphorylation at Y207 (P = 0.062);Loss of phosphorylation at Y207 (P = 0.062);Loss of phosphorylation at Y207 (P = 0.062);Loss of phosphorylation at Y207 (P = 0.062);
MVP		0.97
MPC		0.62
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104893849; hg19: chr4-146567195;