chr13-100449305-GGTAA-G

Variant names:

• chr13-100449305-GGTAA-G
• rs794727334
• NM_000282.4:c.1899+4_1899+7delAGTA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Moderate PS3 PP5_Very_Strong

The ENST00000376285.6(PCCA):​c.1899+1_1899+4delGTAA variant causes a splice donor, splice region, intron change. The variant allele was found at a frequency of 0.0000278 in 1,508,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001231679: RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. PMID:9385377, 10101253, 10780784, 22033733" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PCCA ENST00000376285.6 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.98
• Publications: 4 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024691358 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 0 (no position change), new splice context is: gtgGTatga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001231679: RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. PMID:9385377, 10101253, 10780784, 22033733; SCV001431999: "In functional studies, the variant resulted in an in-frame deletion of 18 amino acids as a result of exon skipping (Richard_1997, Clavero_2004)."; SCV001984842: Splicing studies in patient's fibroblasts demonstrated that this variant leads to skipping of exon 21 and residual low levels of normal splicing (PMID: 9385377, 15235904).
• PP5: Variant 13-100449305-GGTAA-G is Pathogenic according to our data. Variant chr13-100449305-GGTAA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1899+4_1899+7delAGTA		splice_region intron	N/A	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.1845+23578_1845+23581delAGTA		intron	N/A	NP_001339534.1
	PCCA	NM_001127692.3		c.1821+4_1821+7delAGTA		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.1899+1_1899+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.2022+1_2022+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.2004+1_2004+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152052 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000590 AC: 9 AN: 152424 AF XY: 0.0000623

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000173

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000155 AC: 21 AN: 1356648 Hom.: 0 AF XY: 0.0000179 AC XY: 12 AN XY: 671598

African (AFR) AF: 0.00 AC: 0 AN: 30762

American (AMR) AF: 0.000198 AC: 7 AN: 35428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24898

East Asian (EAS) AF: 0.00 AC: 0 AN: 35476

South Asian (SAS) AF: 0.00 AC: 0 AN: 77878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.0000135 AC: 14 AN: 1040862

Other (OTH) AF: 0.00 AC: 0 AN: 56550

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152052 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00125 AC: 19 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Propionic acidemia (6)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 0

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

Other links and lift over

dbSNP: rs794727334; hg19: chr13-101101559;