rs920825350

Variant names:

• chr4-145646087-A-G
• rs920825350
• NM_172250.3:c.664A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_172250.3(MMAA):​c.664A>G​(p.Arg222Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R222R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MMAA NM_172250.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 2.44
• Publications: 1 publications found

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]

MMAA Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblA type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, ClinGen, Ambry Genetics, G2P

ENSG00000248356 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_172250.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 4-145646087-A-G is Pathogenic according to our data. Variant chr4-145646087-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522648.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172250.3. 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
	MMAA	NM_172250.3	MANE Select	c.664A>G	p.Arg222Gly	missense	Exon 4 of 7	NP_758454.1	Q8IVH4
	MMAA	NM_001375644.1		c.664A>G	p.Arg222Gly	missense	Exon 4 of 7	NP_001362573.1	Q8IVH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAA	ENST00000649156.2	MANE Select	c.664A>G	p.Arg222Gly	missense	Exon 4 of 7	ENSP00000497008.1	Q8IVH4
	MMAA	ENST00000511969.4	TSL:1	n.664A>G		non_coding_transcript_exon	Exon 3 of 5	ENSP00000427422.1	D6RIS5
	MMAA	ENST00000541599.5	TSL:5	c.664A>G	p.Arg222Gly	missense	Exon 4 of 7	ENSP00000442284.3	Q8IVH4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251422 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000342 AC: 5 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111952

Other (OTH) AF: 0.0000662 AC: 4 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Methylmalonic aciduria, cblA type (3)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.67		Gain of catalytic residue at G219 (P = 0.0615)
MVP		0.98
MPC		0.62
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.93
Mutation Taster		=27/73	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs920825350; hg19: chr4-146567239; COSMIC: COSV55580405; COSMIC: COSV55580405;