NM_000282.4:c.627A>G

Variant names:

• chr13-100235868-A-G
• rs538229
• NM_000282.4:c.627A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000282.4(PCCA):​c.627A>G​(p.Ala209Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.163 in 1,601,178 control chromosomes in the GnomAD database, including 22,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1677 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21110 hom.)
• Consequence: PCCA NM_000282.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.13
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 13-100235868-A-G is Benign according to our data. Variant chr13-100235868-A-G is described in ClinVar as Benign. ClinVar VariationId is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

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.627A>G	p.Ala209Ala	synonymous	Exon 8 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.627A>G	p.Ala209Ala	synonymous	Exon 8 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.549A>G	p.Ala183Ala	synonymous	Exon 7 of 23	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.627A>G	p.Ala209Ala	synonymous	Exon 8 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.627A>G	p.Ala209Ala	synonymous	Exon 8 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.732A>G	p.Ala244Ala	synonymous	Exon 9 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21555 AN: 152104 Hom.: 1677 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.147 AC: 37067 AN: 251336 AF XY: 0.150

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.00870

Gnomad FIN exome AF: 0.0961

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.165 AC: 239420 AN: 1448956 Hom.: 21110 Cov.: 27 AF XY: 0.165 AC XY: 119037 AN XY: 721788

African (AFR) AF: 0.102 AC: 3382 AN: 33262

American (AMR) AF: 0.167 AC: 7446 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4511 AN: 26010

East Asian (EAS) AF: 0.00614 AC: 243 AN: 39578

South Asian (SAS) AF: 0.151 AC: 12985 AN: 85972

European-Finnish (FIN) AF: 0.103 AC: 5521 AN: 53374

Middle Eastern (MID) AF: 0.195 AC: 1119 AN: 5732

European-Non Finnish (NFE) AF: 0.177 AC: 194724 AN: 1100354

Other (OTH) AF: 0.158 AC: 9489 AN: 59980

GnomAD4 genome AF: 0.142 AC: 21567 AN: 152222 Hom.: 1677 Cov.: 32 AF XY: 0.137 AC XY: 10167 AN XY: 74424

African (AFR) AF: 0.105 AC: 4366 AN: 41540

American (AMR) AF: 0.160 AC: 2450 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 539 AN: 3468

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5180

South Asian (SAS) AF: 0.133 AC: 641 AN: 4828

European-Finnish (FIN) AF: 0.0917 AC: 972 AN: 10598

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12083 AN: 68000

Other (OTH) AF: 0.146 AC: 308 AN: 2114

Alfa AF: 0.169 Hom.: 1652

Bravo AF: 0.147

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	5	Propionic acidemia (5)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs538229; hg19: chr13-100888122; COSMIC: COSV66191930;