rs587776889

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_015506.3(MMACHC):​c.609G>A​(p.Trp203Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 3.61
Variant links:
Genes affected
MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.283 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45508975-G-A is Pathogenic according to our data. Variant chr1-45508975-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45508975-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MMACHCNM_015506.3 linkuse as main transcriptc.609G>A p.Trp203Ter stop_gained 4/4 ENST00000401061.9 NP_056321.2
MMACHCNM_001330540.2 linkuse as main transcriptc.438G>A p.Trp146Ter stop_gained 4/4 NP_001317469.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MMACHCENST00000401061.9 linkuse as main transcriptc.609G>A p.Trp203Ter stop_gained 4/42 NM_015506.3 ENSP00000383840 P1
MMACHCENST00000616135.1 linkuse as main transcriptc.438G>A p.Trp146Ter stop_gained 4/52 ENSP00000478859

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000768
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000441
AC:
11
AN:
249554
Hom.:
0
AF XY:
0.0000443
AC XY:
6
AN XY:
135394
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000556
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000770
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000474
Hom.:
0
Bravo
AF:
0.000102
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cobalamin C disease Pathogenic:15
Pathogenic, criteria provided, single submitterclinical testingGenetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou UniversityMay 13, 2021- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 13, 2017Variant summary: The MMACHC c.609G>A (p.Trp203X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121366 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been reported in numerous affected individuals in the homozygous and compound heterozygous state, and there is evidence the variant may be a founder mutation in the Chinese population (Lerner-Ellis_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PM2_Supporting+PM3_VeryStrong+PP4+PVS1_Strong -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000441, PM2). he variant was observed in trans with a pathogenic variant (NM_015506.2: c.394C>T) as compound heterozygous (3billion dataset, PM3). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000030800.12). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedresearchNeurology Department, Peking University First HospitalApr 23, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2010- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 02, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCounsylMar 17, 2017- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 28, 2024- -
Pathogenic, criteria provided, single submitterclinical testingPrecision Medicine Center, Zhengzhou UniversityDec 01, 2023PVS1,PM2_p,PM3 -
Pathogenic, no assertion criteria providedcase-controlBiochemistry Laboratory of CDMU, Chengde Medical University-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024This sequence change creates a premature translational stop signal (p.Trp203*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs587776889, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with MMACHC-related conditions (PMID: 16311595, 20631720, 23954310, 25772322, 27383490, 28327205). ClinVar contains an entry for this variant (Variation ID: 30800). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBeijing Key Laboratry for Genetics of Birth Defects, Beijing Children's HospitalFeb 28, 2020- -
Pathogenic, no assertion criteria providedclinical testingDevelopmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University-- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 17, 2024Nonsense variant predicted to result in protein truncation, as the last 80 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 26283149, 26149271, 34704411, 33691766, 34474183, 34102818, 35361390, 35085585, 23591356, 22995991, 20631720, 21055272, 26563984, 27383490, 27751223, 29042959, 28327205, 29581464, 29340559, 29068997, 30712249, 29045954, 31178897, 30863077, 30564975, 31574870, 31203424, 31697851, 31965297, 30157807, 32443968, 31998365, 29731766, 32005694, 34539730, 32957924, 32943488, 32901917, 32712949, 32778825, 33473346, 33914258, 34076870, 33982424, 35578252, 35935352, 35709987, 34953813, 33327995, 35193651, 31328266, 35660814, 16311595, 32746869) -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 25, 2017The p.Trp203Ter variant creates a termination codon in the MMACHC protein at codon 203 in exon 4 which is predicted to result in a truncated or absent protein product. In a cohort of 204 individuals suspected with inborn errors in cobalamin metabolism, the p.Trp203Ter was identified in the MMACHC gene from 7 individuals with pathogenic bi-allelic variants, including 5 homozygotes (Lerner-Ellis et. al. 2006). Furthermore, the p.Trp203Ter was observed in 52 out of 71 Chinese patients, including 15 homozygotes with elevated methylmalonic aciduria (MMA) and homocystinuria (HC), whereby haplotype analysis determined that it may have been caused by a founder effect in this population (Liu et. al. 2010). This variant is reported in ClinVar (Variation ID: 30800) as pathogenic. It is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 10 out of 246,224 chromosomes). Based on these observations the p.Trp203Ter is pathogenic. -
Methylmalonic acidemia with homocystinuria cblC Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Disorders of Intracellular Cobalamin Metabolism Other:1
not provided, no classification providedliterature onlyGeneReviews-Common in people of Chinese ancestry. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
39
DANN
Uncertain
0.99
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
D
Vest4
0.73
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776889; hg19: chr1-45974647; COSMIC: COSV105011595; COSMIC: COSV105011595; API