NM_015702.3:c.228dupG

Variant names:

• chr2-149579574-T-TC
• rs864309741
• NM_015702.3:c.228dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015702.3(MMADHC):​c.228dupG​(p.Asn77GlufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMADHC NM_015702.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.889
• Publications: 0 publications found

Genes affected

MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

MMADHC Gene-Disease associations (from GenCC):

• inborn disorder of cobalamin metabolism and transport

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• methylmalonic aciduria and homocystinuria type cblD

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-149579574-T-TC is Pathogenic according to our data. Variant chr2-149579574-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 219000.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015702.3. 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
	MMADHC	NM_015702.3	MANE Select	c.228dupG	p.Asn77GlufsTer5	frameshift	Exon 4 of 8	NP_056517.1	Q9H3L0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMADHC	ENST00000303319.10	TSL:1 MANE Select	c.228dupG	p.Asn77GlufsTer5	frameshift	Exon 4 of 8	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.228dupG	p.Asn77GlufsTer5	frameshift	Exon 4 of 9	ENSP00000604308.1
	MMADHC	ENST00000422782.2	TSL:5	c.228dupG	p.Asn77GlufsTer5	frameshift	Exon 4 of 9	ENSP00000408331.2	F8WEC0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
-	-	-	Methylmalonic aciduria and homocystinuria type cblD (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.89
Mutation Taster		=0/200	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: rs864309741; hg19: chr2-150436088;