rs13402787
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_015702.3(MMADHC):c.478+6T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,576,222 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.015 ( 58 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 64 hom. )
Consequence
MMADHC
NM_015702.3 splice_donor_region, intron
NM_015702.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0004755
2
Clinical Significance
Conservation
PhyloP100: 1.00
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 2-149576431-A-C is Benign according to our data. Variant chr2-149576431-A-C is described in ClinVar as [Benign]. Clinvar id is 331378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-149576431-A-C is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMADHC | NM_015702.3 | c.478+6T>G | splice_donor_region_variant, intron_variant | ENST00000303319.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMADHC | ENST00000303319.10 | c.478+6T>G | splice_donor_region_variant, intron_variant | 1 | NM_015702.3 | P1 | |||
MMADHC | ENST00000422782.2 | c.478+6T>G | splice_donor_region_variant, intron_variant | 5 | |||||
MMADHC | ENST00000428879.5 | c.478+6T>G | splice_donor_region_variant, intron_variant | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0151 AC: 2295AN: 152168Hom.: 56 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00392 AC: 986AN: 251286Hom.: 20 AF XY: 0.00283 AC XY: 384AN XY: 135826
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GnomAD4 exome AF: 0.00158 AC: 2255AN: 1423936Hom.: 64 Cov.: 24 AF XY: 0.00134 AC XY: 956AN XY: 711002
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GnomAD4 genome ? AF: 0.0152 AC: 2315AN: 152286Hom.: 58 Cov.: 32 AF XY: 0.0147 AC XY: 1098AN XY: 74460
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria and homocystinuria type cblD Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 08, 2023 | - - |
Disorders of Intracellular Cobalamin Metabolism Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at