rs864309729

Positions:

• chr4-145642485-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_172250.3(MMAA):​c.562G>C​(p.Gly188Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MMAA NM_172250.3 missense, splice_region
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.35

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]

ENSG00000248356 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 4-145642485-G-C is Pathogenic according to our data. Variant chr4-145642485-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218975.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAA	NM_172250.3	c.562G>C	p.Gly188Arg	missense_variant, splice_region_variant	3/7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1	c.562G>C	p.Gly188Arg	missense_variant, splice_region_variant	3/7		NP_001362573.1
MMAA	XM_011531684.4	c.562G>C	p.Gly188Arg	missense_variant, splice_region_variant	3/7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2	c.562G>C	p.Gly188Arg	missense_variant, splice_region_variant	3/7		NM_172250.3	ENSP00000497008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;D;D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;.;.;D;D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;H;H;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.6	.;.;D;.;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;D
Polyphen		1.0	D;.;D;D;D;.
Vest4		0.99, 0.99
MutPred		0.98		Loss of glycosylation at S189 (P = 0.0472);Loss of glycosylation at S189 (P = 0.0472);Loss of glycosylation at S189 (P = 0.0472);Loss of glycosylation at S189 (P = 0.0472);Loss of glycosylation at S189 (P = 0.0472);Loss of glycosylation at S189 (P = 0.0472);
MVP		0.99
MPC		0.61
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864309729; hg19: chr4-146563637;