rs1029096863

Variant names:

• chr4-145646009-C-T
• rs1029096863
• NM_172250.3:c.586C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-145646009-C-T
• chr4-145646009-C-G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_172250.3(MMAA):​c.586C>T​(p.Arg196*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000242 in 1,613,664 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001363089: At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: MMAA NM_172250.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.67
• Publications: 2 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: Pathogenic. The variant received 22 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: SCV001363089: At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-145646009-C-T is Pathogenic according to our data. Variant chr4-145646009-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 466217.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.586C>T	p.Arg196*	stop_gained	Exon 4 of 7	NP_758454.1	Q8IVH4
	MMAA	NM_001375644.1		c.586C>T	p.Arg196*	stop_gained	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.586C>T	p.Arg196*	stop_gained	Exon 4 of 7	ENSP00000497008.1	Q8IVH4
	MMAA	ENST00000511969.4	TSL:1	n.586C>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000427422.1	D6RIS5
	MMAA	ENST00000541599.5	TSL:5	c.586C>T	p.Arg196*	stop_gained	Exon 4 of 7	ENSP00000442284.3	Q8IVH4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251370 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727170

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

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

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74210

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Methylmalonic aciduria, cblA type (7)
1	-	-	Methylmalonic acidemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.7
Vest4		0.96
GERP RS		4.6
Mutation Taster		=2/198	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: rs1029096863; hg19: chr4-146567161; COSMIC: COSV99849569; COSMIC: COSV99849569;