1-45500340-C-G

Position:

• chr1-45500340-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_015506.3(MMACHC):​c.8C>G​(p.Pro3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P3P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.541

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a chain Cyanocobalamin reductase / alkylcobalamin dealkylase (size 281) in uniprot entity MMAC_HUMAN there are 49 pathogenic changes around while only 14 benign (78%) in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045140862).
• BP6: Variant 1-45500340-C-G is Benign according to our data. Variant chr1-45500340-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1545615.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.8C>G	p.Pro3Arg	missense_variant	1/4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.-215C>G		5_prime_UTR_variant	1/4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.8C>G	p.Pro3Arg	missense_variant	1/4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1	c.-164C>G		upstream_gene_variant		2		ENSP00000478859.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249574 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135398

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461790 Hom.: 0 Cov.: 30 AF XY: 0.0000523 AC XY: 38 AN XY: 727194

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74324

Gnomad4 AFR AF: 0.000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000999 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 04, 2023	- -

Cobalamin C disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.045	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.38
Sift	Benign	0.091	T
Sift4G	Uncertain	0.024	D
Polyphen		0.68	P
Vest4		0.19
MVP		0.97
MPC		0.012
ClinPred		0.089	T
GERP RS		4.9
Varity_R		0.24
gMVP		0.42

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

Other links and lift over

dbSNP: rs201807738; hg19: chr1-45966012;