1-45504774-C-T

Variant names:

• chr1-45504774-C-T
• rs12029322
• NM_015506.3:c.82-2582C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015506.3(MMACHC):​c.82-2582C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,980 control chromosomes in the GnomAD database, including 4,134 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4134 hom., cov: 31)
• Consequence: MMACHC NM_015506.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.82-2582C>T		intron_variant	Intron 1 of 3	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.-141-2531C>T		intron_variant	Intron 1 of 3		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.82-2582C>T		intron_variant	Intron 1 of 3	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1	c.-90-2582C>T		intron_variant	Intron 1 of 4	2		ENSP00000478859.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34945 AN: 151862 Hom.: 4118 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.230 AC: 34997 AN: 151980 Hom.: 4134 Cov.: 31 AF XY: 0.229 AC XY: 17016 AN XY: 74244

African (AFR) AF: 0.214 AC: 8891 AN: 41456

American (AMR) AF: 0.291 AC: 4437 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3464

East Asian (EAS) AF: 0.334 AC: 1723 AN: 5156

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4820

European-Finnish (FIN) AF: 0.188 AC: 1980 AN: 10550

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15092 AN: 67960

Other (OTH) AF: 0.262 AC: 551 AN: 2106

Alfa AF: 0.221 Hom.: 5678

Bravo AF: 0.238

Asia WGS AF: 0.313 AC: 1091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.76
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs12029322; hg19: chr1-45970446;