rs397509364

Variant names:

• chr2-149571078-TACTC-T
• rs397509364
• NM_015702.3:c.696+3_696+6delGAGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015702.3(MMADHC):​c.696+3_696+6delGAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMADHC NM_015702.3 splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.79
• 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: 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-149571078-TACTC-T is Pathogenic according to our data. Variant chr2-149571078-TACTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 769.Status of the report is no_assertion_criteria_provided, 0 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.696+3_696+6delGAGT		splice_region intron	N/A	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.696+3_696+6delGAGT		splice_region intron	N/A	ENSP00000301920.5	Q9H3L0
	MMADHC	ENST00000934249.1		c.819+3_819+6delGAGT		splice_region intron	N/A	ENSP00000604308.1
	MMADHC	ENST00000422782.2	TSL:5	c.798+3_798+6delGAGT		splice_region intron	N/A	ENSP00000408331.2	F8WEC0

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

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Methylmalonic aciduria and homocystinuria type cblD (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 7

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

Other links and lift over

dbSNP: rs397509364; hg19: chr2-150427592;