22-43133308-G-C

Variant names:

• chr22-43133308-G-C
• rs13815
• NM_173467.5:c.908C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173467.5(MCAT):​c.908C>G​(p.Ala303Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,613,888 control chromosomes in the GnomAD database, including 341,375 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A303T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.55 (25273 hom., cov: 32)
  • Exomes 𝑓: 0.65 (316102 hom.)
• Consequence: MCAT NM_173467.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05
• Publications: 52 publications found

Genes affected

MCAT (HGNC:29622): (malonyl-CoA-acyl carrier protein transacylase) The protein encoded by this gene is found exclusively in the mitochondrion, where it catalyzes the transfer of a malonyl group from malonyl-CoA to the mitochondrial acyl carrier protein. The encoded protein may be part of a fatty acid synthase complex that is more like the type II prokaryotic and plastid complexes rather than the type I human cytosolic complex. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2012]

MCAT Gene-Disease associations (from GenCC):

• autosomal recessive optic atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.712513E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCAT	NM_173467.5	c.908C>G	p.Ala303Gly	missense_variant	Exon 4 of 4	ENST00000290429.11	NP_775738.3
MCAT	NR_046423.1	n.773C>G		non_coding_transcript_exon_variant	Exon 3 of 3
MCAT	NM_014507.3	c.*147C>G		3_prime_UTR_variant	Exon 3 of 3		NP_055322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCAT	ENST00000290429.11	c.908C>G	p.Ala303Gly	missense_variant	Exon 4 of 4	1	NM_173467.5	ENSP00000290429.5
MCAT	ENST00000327555.5	c.*147C>G		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000331306.5

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83298 AN: 151916 Hom.: 25267 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.567

GnomAD2 exomes AF: 0.606 AC: 152471 AN: 251488 AF XY: 0.609

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.569

Gnomad EAS exome AF: 0.599

Gnomad FIN exome AF: 0.697

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.652 AC: 953452 AN: 1461854 Hom.: 316102 Cov.: 72 AF XY: 0.650 AC XY: 472524 AN XY: 727228

African (AFR) AF: 0.258 AC: 8640 AN: 33480

American (AMR) AF: 0.555 AC: 24837 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 14936 AN: 26136

East Asian (EAS) AF: 0.591 AC: 23479 AN: 39700

South Asian (SAS) AF: 0.528 AC: 45563 AN: 86258

European-Finnish (FIN) AF: 0.697 AC: 37242 AN: 53416

Middle Eastern (MID) AF: 0.538 AC: 3102 AN: 5768

European-Non Finnish (NFE) AF: 0.682 AC: 758365 AN: 1111976

Other (OTH) AF: 0.617 AC: 37288 AN: 60396

GnomAD4 genome AF: 0.548 AC: 83347 AN: 152034 Hom.: 25273 Cov.: 32 AF XY: 0.546 AC XY: 40597 AN XY: 74318

African (AFR) AF: 0.279 AC: 11552 AN: 41452

American (AMR) AF: 0.539 AC: 8239 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2025 AN: 3464

East Asian (EAS) AF: 0.610 AC: 3148 AN: 5160

South Asian (SAS) AF: 0.511 AC: 2461 AN: 4814

European-Finnish (FIN) AF: 0.712 AC: 7533 AN: 10586

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46300 AN: 67966

Other (OTH) AF: 0.567 AC: 1197 AN: 2112

Alfa AF: 0.647 Hom.: 22843

Bravo AF: 0.528

TwinsUK AF: 0.674 AC: 2500

ALSPAC AF: 0.688 AC: 2653

ESP6500AA AF: 0.291 AC: 1280

ESP6500EA AF: 0.680 AC: 5845

ExAC AF: 0.604 AC: 73380

Asia WGS AF: 0.523 AC: 1815 AN: 3478

EpiCase AF: 0.669

EpiControl AF: 0.658

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.54
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0000067	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.36	N
PhyloP100		3.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	4.5	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.30
ClinPred		0.0054	T
GERP RS		5.5
Varity_R		0.087
gMVP		0.67
Mutation Taster		=90/10	polymorphism (auto)

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: rs13815; hg19: chr22-43529314; COSMIC: COSV51792539; COSMIC: COSV51792539;