1-45511415-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_181697.3(PRDX1):c.515-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 1,459,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PRDX1
NM_181697.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.87

Publications

7 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: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-45511415-C-A is Pathogenic according to our data. Variant chr1-45511415-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 495209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.*2200C>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000401061.9	NP_056321.2	Q9Y4U1
PRDX1	NM_181697.3 link	c.515-1G>T		splice_acceptor_variant, intron_variant	Intron 5 of 5	ENST00000319248.13	NP_859048.1	Q06830A0A384NPQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 link	c.*2200C>A		3_prime_UTR_variant	Exon 4 of 4	2	NM_015506.3	ENSP00000383840.4		Q9Y4U1
PRDX1	ENST00000319248.13 link	c.515-1G>T		splice_acceptor_variant, intron_variant	Intron 5 of 5	1	NM_181697.3	ENSP00000361152.5		Q06830

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000401

AC:

AN:

249150

AF XY:

0.0000371

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1459754

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.00

AC:

AN:

44278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

85936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1110998

Other (OTH)

AF:

0.00

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000194

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 495209). This variant has been observed in individual(s) with epi-cobalamin C deficiency (PMID: 29302025, 32099815, 34215320). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant in the MMACHC gene. This variant is present in population databases (rs751828470, gnomAD 0.009%). This sequence change falls in intron 5 of the PRDX1 gene. It does not directly change the encoded amino acid sequence of the PRDX1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of PRDX1 exon 6 and aberrant antisense transcription that results in MMACHC promoter hypermethylation and MMACHC silencing (PMID: 29302025). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cobalamin C disease

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC

Pathogenic:1

Nov 03, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.9

GERP RS

4.9

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.62

Position offset: -10

DS_AL_spliceai

0.99

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-45511415-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over