Genetic Variant MACF1:p.Ile1599Val (chr1-39331383-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001394062.1(MACF1):c.4795A>G(p.Ile1599Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,782 control chromosomes in the GnomAD database, including 37,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2824 hom., cov: 31)

Exomes 𝑓: 0.21 ( 34444 hom. )

Consequence

MACF1
NM_001394062.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0980

Publications

33 publications found

Variant links:

Genes affected

MACF1 (HGNC:13664): (microtubule actin crosslinking factor 1) This gene encodes a large protein containing numerous spectrin and leucine-rich repeat (LRR) domains. The encoded protein is a member of a family of proteins that form bridges between different cytoskeletal elements. This protein facilitates actin-microtubule interactions at the cell periphery and couples the microtubule network to cellular junctions. Alternative splicing results in multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, May 2013]

MACF1 Gene-Disease associations (from GenCC):

lissencephaly 9 with complex brainstem malformation
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics
lissencephaly spectrum disorder with complex brainstem malformation
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MACF1 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=0.0036052167).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_001394062.1 link	c.4795A>G	p.Ile1599Val	missense_variant	Exon 37 of 101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5 link	c.4629+4030A>G		intron_variant	Intron 35 of 92		NP_036222.3	Q9UPN3-2Q6ZSD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6 link	c.4795A>G	p.Ile1599Val	missense_variant	Exon 37 of 101	5	NM_001394062.1	ENSP00000455274.1		H3BPE1

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26125

AN:

151846

Hom.:

2826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.221

Gnomad OTH

AF:

0.185

GnomAD2 exomes

AF:

0.219

AC:

55044

AN:

251250

AF XY:

0.217

show subpopulations

Gnomad AFR exome

AF:

0.0399

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.221

Gnomad OTH exome

AF:

0.202

GnomAD4 exome

AF:

0.213

AC:

311365

AN:

1461816

Hom.:

34444

Cov.:

AF XY:

0.212

AC XY:

154338

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0349

AC:

1169

AN:

33478

American (AMR)

AF:

0.286

AC:

12802

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6193

AN:

26134

East Asian (EAS)

AF:

0.282

AC:

11186

AN:

39698

South Asian (SAS)

AF:

0.183

AC:

15808

AN:

86242

European-Finnish (FIN)

AF:

0.208

AC:

11125

AN:

53412

Middle Eastern (MID)

AF:

0.160

AC:

925

AN:

5764

European-Non Finnish (NFE)

AF:

0.216

AC:

240103

AN:

1111976

Other (OTH)

AF:

0.200

AC:

12054

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

14829

29657

44486

59314

74143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8190

16380

24570

32760

40950

<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:

0.172

AC:

26117

AN:

151966

Hom.:

2824

Cov.:

AF XY:

0.171

AC XY:

12729

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.0416

AC:

1727

AN:

41474

American (AMR)

AF:

0.223

AC:

3403

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

794

AN:

3470

East Asian (EAS)

AF:

0.285

AC:

1463

AN:

5142

South Asian (SAS)

AF:

0.182

AC:

874

AN:

4802

European-Finnish (FIN)

AF:

0.216

AC:

2277

AN:

10554

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.221

AC:

15029

AN:

67936

Other (OTH)

AF:

0.184

AC:

388

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1021

2042

3062

4083

5104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.204

Hom.:

10465

Bravo

AF:

0.170

TwinsUK

AF:

0.212

AC:

787

ALSPAC

AF:

0.207

AC:

799

ESP6500AA

AF:

0.0463

AC:

204

ESP6500EA

AF:

0.226

AC:

1945

ExAC

AF:

0.212

AC:

25773

Asia WGS

AF:

0.211

AC:

732

AN:

3478

EpiCase

AF:

0.215

EpiControl

AF:

0.221

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.031

T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.098

PROVEAN

Benign

-0.16

N;N;N;N

REVEL

Benign

0.074

Sift

Benign

0.14

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.036

ClinPred

0.0015

GERP RS

-7.8

Varity_R

0.019

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over