rs16832550

chr1-45509104-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015506.3(MMACHC):c.738C>T(p.Pro246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,612,282 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P246P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (58 hom.)
• Consequence: MMACHC NM_015506.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.19

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-45509104-C-T is Benign according to our data. Variant chr1-45509104-C-T is described in ClinVar as [Benign]. Clinvar id is 138239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45509104-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1911/152240) while in subpopulation AFR AF= 0.0395 (1640/41542). AF 95% confidence interval is 0.0379. There are 32 homozygotes in gnomad4. There are 905 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMACHC	NM_015506.3	c.738C>T	p.Pro246=	synonymous_variant	4/4	ENST00000401061.9
MMACHC	NM_001330540.2	c.567C>T	p.Pro189=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMACHC	ENST00000401061.9	c.738C>T	p.Pro246=	synonymous_variant	4/4	2	NM_015506.3	P1
MMACHC	ENST00000616135.1	c.567C>T	p.Pro189=	synonymous_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1911 AN: 152122 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00503 AC: 1243 AN: 247118 Hom.: 39 AF XY: 0.00407 AC XY: 545 AN XY: 134054

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000792

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000964

Gnomad OTH exome AF: 0.00600

GnomAD4 exome AF: 0.00224 AC: 3276 AN: 1460042 Hom.: 58 Cov.: 32 AF XY: 0.00208 AC XY: 1510 AN XY: 726276

Gnomad4 AFR exome AF: 0.0414

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.0126 AC: 1911 AN: 152240 Hom.: 32 Cov.: 32 AF XY: 0.0122 AC XY: 905 AN XY: 74440

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00556 Hom.: 13

Bravo AF: 0.0143

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 02, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.69
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16832550; hg19: chr1-45974776;