rs764045674

Variant names:

• chr13-100307261-GTTAGT-G
• rs764045674
• NM_000282.4:c.1353+5_1353+9delGTTTA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000376285.6(PCCA):​c.1353+2_1353+6delTTAGT variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000042 in 1,429,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: PCCA ENST00000376285.6 splice_donor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.21
• Publications: 1 publications found

Genes affected

PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

PCCA Gene-Disease associations (from GenCC):

• propionic acidemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03155007 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-100307261-GTTAGT-G is Pathogenic according to our data. Variant chr13-100307261-GTTAGT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254165.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376285.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	NM_000282.4	MANE Select	c.1353+5_1353+9delGTTTA		splice_region intron	N/A	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.1353+5_1353+9delGTTTA		splice_region intron	N/A	NP_001339534.1
	PCCA	NM_001127692.3		c.1275+5_1275+9delGTTTA		splice_region intron	N/A	NP_001121164.1	P05165-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1353+2_1353+6delTTAGT		splice_donor splice_region intron	N/A	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.1476+2_1476+6delTTAGT		splice_donor splice_region intron	N/A	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.1458+2_1458+6delTTAGT		splice_donor splice_region intron	N/A	ENSP00000551699.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250478 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000420 AC: 6 AN: 1429704 Hom.: 0 AF XY: 0.00000561 AC XY: 4 AN XY: 713318

African (AFR) AF: 0.00 AC: 0 AN: 32888

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39508

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083266

Other (OTH) AF: 0.00 AC: 0 AN: 59310

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Propionic acidemia (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs764045674;

hg19: chr13-100959515;