chr1-45500346-T-C

Variant names:

• chr1-45500346-T-C
• rs780981680
• NM_015506.3:c.14T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_015506.3(MMACHC):​c.14T>C​(p.Val5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V5D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.966
• Publications: 0 publications found

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]

MMACHC Gene-Disease associations (from GenCC):

• methylmalonic aciduria and homocystinuria type cblC

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 38 pathogenic changes around while only 16 benign (70%) in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -1.0759 (below the threshold of 3.09). Trascript score misZ: -0.13772 (below the threshold of 3.09). GenCC associations: The gene is linked to methylmalonic aciduria and homocystinuria type cblC.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16790318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.-209T>C		5_prime_UTR_variant	Exon 1 of 4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1	c.-158T>C		5_prime_UTR_variant	Exon 1 of 5	2		ENSP00000478859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.3	L
PhyloP100		0.97
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.29
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0070	B
Vest4		0.16
MutPred		0.36		Loss of methylation at K4 (P = 0.0391);
MVP		0.97
MPC		0.014
ClinPred		0.54	D
GERP RS		3.4
PromoterAI		0.022	Neutral
Varity_R		0.25
gMVP		0.63
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs780981680; hg19: chr1-45966018;