rs864309742

chr2-149582220-A-AAT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015702.3(MMADHC):c.60_61insAT(p.Leu21IlefsTer2) 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 (★).

• 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: 0.547

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-149582220-A-AAT is Pathogenic according to our data. Variant chr2-149582220-A-AAT is described in ClinVar as [Pathogenic]. Clinvar id is 219001.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMADHC	NM_015702.3	c.60_61insAT	p.Leu21IlefsTer2	frameshift_variant	3/8	ENST00000303319.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMADHC	ENST00000303319.10	c.60_61insAT	p.Leu21IlefsTer2	frameshift_variant	3/8	1	NM_015702.3	P1
MMADHC	ENST00000422782.2	c.60_61insAT	p.Leu21IlefsTer2	frameshift_variant	3/9	5
MMADHC	ENST00000428879.5	c.60_61insAT	p.Leu21IlefsTer2	frameshift_variant	2/7	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 09, 2019	This variant has been observed in an individual affected with methylmalonic acidemia (PMID: 22156578). ClinVar contains an entry for this variant (Variation ID: 219001). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MMADHC are known to be pathogenic (PMID: 18385497). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu21Ilefs*2) in the MMADHC gene. It is expected to result in an absent or disrupted protein product. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs864309742; hg19: chr2-150438734;