rs118169528

Variant names:

• chr13-100368504-G-T
• rs118169528
• NM_000282.4:c.1676G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-100368504-G-T
• chr13-100368504-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000282.4(PCCA):​c.1676G>T​(p.Trp559Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000892 in 1,608,618 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (22 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:4
• Conservation: PhyloP100: 6.49
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008779764).
• BP6: Variant 13-100368504-G-T is Benign according to our data. Variant chr13-100368504-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218258.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00118 (178/151316) while in subpopulation EAS AF = 0.0318 (162/5092). AF 95% confidence interval is 0.0278. There are 1 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 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.1676G>T	p.Trp559Leu	missense	Exon 19 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.1676G>T	p.Trp559Leu	missense	Exon 19 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.1598G>T	p.Trp533Leu	missense	Exon 18 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.1676G>T	p.Trp559Leu	missense	Exon 19 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.1799G>T	p.Trp600Leu	missense	Exon 20 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.1781G>T	p.Trp594Leu	missense	Exon 20 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 177 AN: 151196 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00302 AC: 760 AN: 251274 AF XY: 0.00266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000863 AC: 1257 AN: 1457302 Hom.: 22 Cov.: 29 AF XY: 0.000813 AC XY: 590 AN XY: 725268

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0282 AC: 1116 AN: 39546

South Asian (SAS) AF: 0.000721 AC: 62 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1108164

Other (OTH) AF: 0.00108 AC: 65 AN: 60240

GnomAD4 genome AF: 0.00118 AC: 178 AN: 151316 Hom.: 1 Cov.: 31 AF XY: 0.00153 AC XY: 113 AN XY: 73816

African (AFR) AF: 0.00 AC: 0 AN: 41246

American (AMR) AF: 0.000132 AC: 2 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0318 AC: 162 AN: 5092

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10344

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67938

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.00125 Hom.: 9

Bravo AF: 0.00193

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	4	2	Propionic acidemia (7)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.017
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.50
Sift	Benign	0.11	T
Sift4G	Uncertain	0.033	D
Polyphen		0.42	B
Vest4		0.81
MVP		0.88
MPC		0.25
ClinPred		0.13	T
GERP RS		4.8
PromoterAI		0.018	Neutral
Varity_R		0.61
gMVP		0.86
Mutation Taster		=77/23	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs118169528; hg19: chr13-101020758; COSMIC: COSV66199369;