rs767060690

Variant names:

• chr13-100307249-A-G
• rs767060690
• NM_000282.4:c.1342A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-100307249-A-G
• chr13-100307249-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000282.4(PCCA):​c.1342A>G​(p.Met448Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,599,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PCCA NM_000282.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.62
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

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.1342A>G	p.Met448Val	missense	Exon 15 of 24	NP_000273.2	P05165-1
	PCCA	NM_001352605.2		c.1342A>G	p.Met448Val	missense	Exon 15 of 23	NP_001339534.1
	PCCA	NM_001127692.3		c.1264A>G	p.Met422Val	missense	Exon 14 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.1342A>G	p.Met448Val	missense	Exon 15 of 24	ENSP00000365462.1	P05165-1
	PCCA	ENST00000881637.1		c.1465A>G	p.Met489Val	missense	Exon 16 of 25	ENSP00000551696.1
	PCCA	ENST00000881640.1		c.1447A>G	p.Met483Val	missense	Exon 16 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250820 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000256 AC: 37 AN: 1447088 Hom.: 0 Cov.: 26 AF XY: 0.0000277 AC XY: 20 AN XY: 720946

African (AFR) AF: 0.000151 AC: 5 AN: 33214

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39586

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5718

European-Non Finnish (NFE) AF: 0.0000218 AC: 24 AN: 1099016

Other (OTH) AF: 0.0000167 AC: 1 AN: 59918

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74474

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Propionic acidemia (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.95	P
Vest4		0.77
MutPred		0.87		Loss of sheet (P = 0.0817)
MVP		0.95
MPC		0.47
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.92
Mutation Taster		=62/38	polymorphism

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: rs767060690; hg19: chr13-100959503;