chr4-145639572-C-T

Variant names:

• chr4-145639572-C-T
• rs104893851
• NM_172250.3:c.433C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_172250.3(MMAA):​c.433C>T​(p.Arg145*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000393 in 1,607,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000699975: "This variant is found in 19/119564 control chromosomes at a frequency of 0.0001589, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0018257). The variant of interest has been reported in many patients from the literature, and R145X is a common disease variant that has been reported to represent 45% of pathogenic MMAA alleles (Lerner-Ellis et al. 2004)." However, the actual evidence fulfilling PS3 is the part mentioning the functional studies: "functional studies showing that patients homozygous for R145X have a 'reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity' (10-29% of WT activity)." So the correct output should be: "functional studies showing that patients homozygous for R145X have a 'reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity' (10-29% of WT activity)."". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: MMAA NM_172250.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: 4.34
• Publications: 21 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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000699975: "This variant is found in 19/119564 control chromosomes at a frequency of 0.0001589, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0018257). The variant of interest has been reported in many patients from the literature, and R145X is a common disease variant that has been reported to represent 45% of pathogenic MMAA alleles (Lerner-Ellis et al. 2004)." However, the actual evidence fulfilling PS3 is the part mentioning the functional studies: "functional studies showing that patients homozygous for R145X have a 'reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity' (10-29% of WT activity)." So the correct output should be: "functional studies showing that patients homozygous for R145X have a 'reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity' (10-29% of WT activity)."
• PP5: Variant 4-145639572-C-T is Pathogenic according to our data. Variant chr4-145639572-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	NP_758454.1	Q8IVH4
	MMAA	NM_001375644.1		c.433C>T	p.Arg145*	stop_gained	Exon 2 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.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	ENSP00000497008.1	Q8IVH4
	MMAA	ENST00000511969.4	TSL:1	n.433C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000427422.1	D6RIS5
	MMAA	ENST00000541599.5	TSL:5	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	ENSP00000442284.3	Q8IVH4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151944 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000161 AC: 40 AN: 248412 AF XY: 0.000179

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000416 AC: 606 AN: 1455800 Hom.: 1 Cov.: 31 AF XY: 0.000401 AC XY: 290 AN XY: 723200

African (AFR) AF: 0.0000904 AC: 3 AN: 33190

American (AMR) AF: 0.0000453 AC: 2 AN: 44138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000317 AC: 27 AN: 85234

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.000486 AC: 539 AN: 1108490

Other (OTH) AF: 0.000532 AC: 32 AN: 60120

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151944 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74178

African (AFR) AF: 0.0000483 AC: 2 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000437

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Methylmalonic aciduria, cblA type (14)
8	-	-	not provided (8)
2	-	-	Methylmalonic acidemia (2)
1	-	-	MMAA-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.3
Vest4		0.90
GERP RS		3.0
Mutation Taster		=1/199	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: rs104893851; hg19: chr4-146560724; COSMIC: COSV55580062; COSMIC: COSV55580062;