13-100449302-A-G

Variant names:

• chr13-100449302-A-G
• rs61760965
• NM_000282.4:c.1896A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000282.4(PCCA):​c.1896A>G​(p.Thr632Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,514,888 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T632T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: PCCA NM_000282.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.445
• Publications: 0 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.048).
• BP6: Variant 13-100449302-A-G is Benign according to our data. Variant chr13-100449302-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459936.
• BP7: Synonymous conserved (PhyloP=0.445 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00116 (1582/1362602) while in subpopulation NFE AF = 0.00141 (1479/1046040). AF 95% confidence interval is 0.00135. There are 2 homozygotes in GnomAdExome4. There are 747 alleles in the male GnomAdExome4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000282.4. 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.1896A>G	p.Thr632Thr	synonymous	Exon 21 of 24	NP_000273.2	P05165-1
	PCCA	NM_001127692.3		c.1818A>G	p.Thr606Thr	synonymous	Exon 20 of 23	NP_001121164.1	P05165-2
	PCCA	NM_001178004.2		c.1896A>G	p.Thr632Thr	synonymous	Exon 21 of 23	NP_001171475.1	P05165-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCA	ENST00000376285.6	TSL:1 MANE Select	c.1896A>G	p.Thr632Thr	synonymous	Exon 21 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.2019A>G	p.Thr673Thr	synonymous	Exon 22 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.2001A>G	p.Thr667Thr	synonymous	Exon 22 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000602 AC: 92 AN: 152710 AF XY: 0.000621

Gnomad AFR exome AF: 0.000344

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000718

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000919

GnomAD4 exome AF: 0.00116 AC: 1582 AN: 1362602 Hom.: 2 Cov.: 23 AF XY: 0.00111 AC XY: 747 AN XY: 674242

African (AFR) AF: 0.000227 AC: 7 AN: 30888

American (AMR) AF: 0.0000282 AC: 1 AN: 35510

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 35530

South Asian (SAS) AF: 0.00 AC: 0 AN: 78120

European-Finnish (FIN) AF: 0.00124 AC: 61 AN: 49218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00141 AC: 1479 AN: 1046040

Other (OTH) AF: 0.000581 AC: 33 AN: 56754

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74468

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000559

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Propionic acidemia (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.4
DANN	Benign	0.78
PhyloP100		0.45
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61760965; hg19: chr13-101101556;