rs397509362

Variant names:

• chr2-149579478-T-TTGATAAAGGTTCTGCTAG
• rs397509362
• NM_015702.3:c.307_324dupCTAGCAGAACCTTTATCA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PP5

The NM_015702.3(MMADHC):​c.307_324dupCTAGCAGAACCTTTATCA​(p.Ser108_Ser109insLeuAlaGluProLeuSer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMADHC NM_015702.3 conservative_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.45
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_015702.3.
• PP5: Variant 2-149579478-T-TTGATAAAGGTTCTGCTAG is Pathogenic according to our data. Variant chr2-149579478-T-TTGATAAAGGTTCTGCTAG is described in ClinVar as Pathogenic. ClinVar VariationId is 766.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.307_324dupCTAGCAGAACCTTTATCA	p.Ser108_Ser109insLeuAlaGluProLeuSer	conservative_inframe_insertion	Exon 4 of 8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.307_324dupCTAGCAGAACCTTTATCA	p.Ser108_Ser109insLeuAlaGluProLeuSer	conservative_inframe_insertion	Exon 4 of 8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.307_324dupCTAGCAGAACCTTTATCA	p.Ser108_Ser109insLeuAlaGluProLeuSer	conservative_inframe_insertion	Exon 4 of 9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.307_324dupCTAGCAGAACCTTTATCA	p.Ser108_Ser109insLeuAlaGluProLeuSer	conservative_inframe_insertion	Exon 3 of 7	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Isolated methylmalonic aciduria cblD type Pathogenic:1

Apr 03, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Methylmalonic aciduria and homocystinuria type cblD Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=53/47	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397509362; hg19: chr2-150435992;