1-45510915-A-G

Position:

• chr1-45510915-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015506.3(MMACHC):​c.*1700A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 155,482 control chromosomes in the GnomAD database, including 42,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41833 hom., cov: 32)
  • Exomes 𝑓: 0.68 (777 hom.)
• Consequence: MMACHC NM_015506.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.771

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]

PRDX1 (HGNC:9352): (peroxiredoxin 1) This gene encodes a member of the peroxiredoxin family of antioxidant enzymes, which reduce hydrogen peroxide and alkyl hydroperoxides. The encoded protein may play an antioxidant protective role in cells, and may contribute to the antiviral activity of CD8(+) T-cells. This protein may have a proliferative effect and play a role in cancer development or progression. Four transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-45510915-A-G is Benign according to our data. Variant chr1-45510915-A-G is described in ClinVar as [Benign]. Clinvar id is 297529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMACHC	NM_015506.3	c.*1700A>G		3_prime_UTR_variant	4/4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2	c.*1700A>G		3_prime_UTR_variant	4/4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9	c.*1700A>G		3_prime_UTR_variant	4/4	2	NM_015506.3	ENSP00000383840.4

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112154 AN: 152046 Hom.: 41804 Cov.: 32

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.734

GnomAD4 exome AF: 0.676 AC: 2243 AN: 3318 Hom.: 777 Cov.: 0 AF XY: 0.683 AC XY: 1204 AN XY: 1762

Gnomad4 AFR exome AF: 0.781

Gnomad4 AMR exome AF: 0.836

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.983

Gnomad4 SAS exome AF: 0.660

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.646

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.738 AC: 112235 AN: 152164 Hom.: 41833 Cov.: 32 AF XY: 0.742 AC XY: 55189 AN XY: 74372

Gnomad4 AFR AF: 0.817

Gnomad4 AMR AF: 0.800

Gnomad4 ASJ AF: 0.734

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.757

Gnomad4 FIN AF: 0.678

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.736

Alfa AF: 0.704 Hom.: 11831

Bravo AF: 0.749

Asia WGS AF: 0.857 AC: 2978 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.54
DANN	Benign	0.68

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: rs1044717; hg19: chr1-45976587;