Genetic Variant MCAT:p.Ala303Gly (chr22-43133308-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.05

Publications

52 publications found

Variant links:

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
optic atrophy 15
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

MCAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173467.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCAT	NM_173467.5	MANE Select	c.908C>G	p.Ala303Gly	missense	Exon 4 of 4	NP_775738.3
MCAT	NM_014507.3		c.*147C>G		3_prime_UTR	Exon 3 of 3	NP_055322.1	Q8IVS2-2
MCAT	NR_046423.1		n.773C>G		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCAT	ENST00000290429.11	TSL:1 MANE Select	c.908C>G	p.Ala303Gly	missense	Exon 4 of 4	ENSP00000290429.5	Q8IVS2-1
MCAT	ENST00000327555.5	TSL:1	c.*147C>G		3_prime_UTR	Exon 3 of 3	ENSP00000331306.5	Q8IVS2-2
MCAT	ENST00000891956.1		c.947C>G	p.Ala316Gly	missense	Exon 5 of 5	ENSP00000562015.1

Frequencies

GnomAD3 genomes

AF:

0.548

AC:

83298

AN:

151916

Hom.:

25267

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.650

AC XY:

472524

AN XY:

727228

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

20462

40924

61385

81847

102309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19198

38396

57594

76792

95990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.548

AC:

83347

AN:

152034

Hom.:

25273

Cov.:

AF XY:

0.546

AC XY:

40597

AN XY:

74318

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1720

3440

5159

6879

8599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.20

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0000067

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.36

PhyloP100

3.0

PrimateAI

Benign

0.39

PROVEAN

Benign

4.5

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.028

MPC

0.30

ClinPred

0.0054

GERP RS

5.5

Varity_R

0.087

gMVP

0.67

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over