rs528744719

Positions:

• chr1-45508250-C-A
• chr1-45508250-C-G
• chr1-45508250-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015506.3(MMACHC):​c.315C>A​(p.Tyr105*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y105Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMACHC NM_015506.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.68

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45508250-C-A is Pathogenic according to our data. Variant chr1-45508250-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1368644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.315C>A	p.Tyr105*	stop_gained	3/4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.144C>A	p.Tyr48*	stop_gained	3/4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.315C>A	p.Tyr105*	stop_gained	3/4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1	c.144C>A	p.Tyr48*	stop_gained	3/5	2		ENSP00000478859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 10, 2021	For these reasons, this variant has been classified as Pathogenic. This nonsense change has been observed in individual(s) with combined methylmalonic aciduria and homocystinuria (PMID: 20631720). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr105*) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 05, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Benign	0.90
Eigen	Benign	-0.72
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
Vest4		0.84
GERP RS		-7.8

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45973922;