1-45510915-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.771

Publications

15 publications found

Variant links:

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 links:

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]

PRDX1 Gene-Disease associations (from GenCC):

methylmalonic aciduria and homocystinuria type cblC
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

PRDX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.*1700A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
PRDX1	NM_181697.3 link	c.*414T>C		downstream_gene_variant		ENST00000319248.13	NP_859048.1	Q06830A0A384NPQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 link	c.*1700A>G		3_prime_UTR_variant	Exon 4 of 4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
PRDX1	ENST00000319248.13 link	c.*414T>C		downstream_gene_variant		1	NM_181697.3	ENSP00000361152.5		Q06830

Frequencies

GnomAD3 genomes

AF:

0.738

AC:

112154

AN:

152046

Hom.:

41804

Cov.:

show subpopulations

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.:

AF XY:

0.683

AC XY:

1204

AN XY:

1762

show subpopulations

African (AFR)

AF:

0.781

AC:

AN:

114

American (AMR)

AF:

0.836

AC:

AN:

110

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

102

AN:

136

East Asian (EAS)

AF:

0.983

AC:

114

AN:

116

South Asian (SAS)

AF:

0.660

AC:

AN:

144

European-Finnish (FIN)

AF:

0.662

AC:

AN:

130

Middle Eastern (MID)

AF:

0.583

AC:

AN:

European-Non Finnish (NFE)

AF:

0.646

AC:

1530

AN:

2368

Other (OTH)

AF:

0.681

AC:

128

AN:

188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.738

AC:

112235

AN:

152164

Hom.:

41833

Cov.:

AF XY:

0.742

AC XY:

55189

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.817

AC:

33944

AN:

41524

American (AMR)

AF:

0.800

AC:

12234

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.734

AC:

2548

AN:

3470

East Asian (EAS)

AF:

0.942

AC:

4890

AN:

5190

South Asian (SAS)

AF:

0.757

AC:

3651

AN:

4826

European-Finnish (FIN)

AF:

0.678

AC:

7164

AN:

10562

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.667

AC:

45329

AN:

67988

Other (OTH)

AF:

0.736

AC:

1558

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1511

3022

4532

6043

7554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.708

Hom.:

15074

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

LINK: link

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.54

(source)

DANN

Benign

0.68

PhyloP100

-0.77

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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1-45510915-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over