chr2-149582255-GCT-G

Variant names:

• chr2-149582255-GCT-G
• rs1553454436
• NM_015702.3:c.24_25delAG

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.24_25delAG​(p.Arg8SerfsTer15) variant causes a frameshift change. 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
• Conservation: PhyloP100: 4.03
• Publications: 1 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: Ambry Genetics, ClinGen
• methylmalonic aciduria and homocystinuria type cblD

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 52 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-149582255-GCT-G is Pathogenic according to our data. Variant chr2-149582255-GCT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 487521.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.24_25delAG	p.Arg8SerfsTer15	frameshift_variant	Exon 3 of 8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.24_25delAG	p.Arg8SerfsTer15	frameshift_variant	Exon 3 of 8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.24_25delAG	p.Arg8SerfsTer15	frameshift_variant	Exon 3 of 9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.24_25delAG	p.Arg8SerfsTer15	frameshift_variant	Exon 2 of 7	2		ENSP00000389060.1

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

Aug 03, 2017

Tianjin Pediatric Research Institute, Tianjin Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553454436; hg19: chr2-150438769;