rs1553454436

chr2-149582255-GCT-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_015702.3(MMADHC):c.24_25del(p.Arg8SerfsTer15) variant causes a frameshift change. 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
• Conservation: PhyloP100: 4.03

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 10 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 34 pathogenic variants in the truncated region.
• PP5: Variant 2-149582255-GCT-G is Pathogenic according to our data. Variant chr2-149582255-GCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 487521.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.24_25del	p.Arg8SerfsTer15	frameshift_variant	3/8	ENST00000303319.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMADHC	ENST00000303319.10	c.24_25del	p.Arg8SerfsTer15	frameshift_variant	3/8	1	NM_015702.3	P1
MMADHC	ENST00000422782.2	c.24_25del	p.Arg8SerfsTer15	frameshift_variant	3/9	5
MMADHC	ENST00000428879.5	c.24_25del	p.Arg8SerfsTer15	frameshift_variant	2/7	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblD Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Tianjin Pediatric Research Institute, Tianjin Children's Hospital

Aug 03, 2017

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553454436; hg19: chr2-150438769;