rs587404

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001394062.1(MACF1):c.19225G>A(p.Ala6409Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,514 control chromosomes in the GnomAD database, including 76,266 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9597 hom., cov: 32)

Exomes 𝑓: 0.30 ( 66669 hom. )

Consequence

MACF1
NM_001394062.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.06

Publications

55 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015339851).

BP6

Variant 1-39442834-G-A is Benign according to our data. Variant chr1-39442834-G-A is described in ClinVar as Benign. ClinVar VariationId is 1266499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_001394062.1 link	c.19225G>A	p.Ala6409Thr	missense_variant	Exon 78 of 101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5 link	c.13048G>A	p.Ala4350Thr	missense_variant	Exon 73 of 93		NP_036222.3	Q9UPN3-2Q6ZSD7
MACF1	NM_001397473.1 link	c.7303G>A	p.Ala2435Thr	missense_variant	Exon 21 of 41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6 link	c.19225G>A	p.Ala6409Thr	missense_variant	Exon 78 of 101	5	NM_001394062.1	ENSP00000455274.1		H3BPE1

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52490

AN:

151924

Hom.:

9568

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.309

Gnomad EAS

AF:

0.359

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.300

AC:

75074

AN:

250478

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.471

Gnomad AMR exome

AF:

0.287

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.299

Gnomad OTH exome

AF:

0.292

GnomAD4 exome

AF:

0.299

AC:

436809

AN:

1461472

Hom.:

66669

Cov.:

AF XY:

0.295

AC XY:

214811

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.478

AC:

16013

AN:

33470

American (AMR)

AF:

0.287

AC:

12827

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

8085

AN:

26132

East Asian (EAS)

AF:

0.325

AC:

12897

AN:

39696

South Asian (SAS)

AF:

0.214

AC:

18429

AN:

86230

European-Finnish (FIN)

AF:

0.254

AC:

13589

AN:

53398

Middle Eastern (MID)

AF:

0.315

AC:

1817

AN:

5764

European-Non Finnish (NFE)

AF:

0.301

AC:

334928

AN:

1111738

Other (OTH)

AF:

0.302

AC:

18224

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

17721

35442

53162

70883

88604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11112

22224

33336

44448

55560

<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:

0.346

AC:

52565

AN:

152042

Hom.:

9597

Cov.:

AF XY:

0.340

AC XY:

25252

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.472

AC:

19553

AN:

41452

American (AMR)

AF:

0.308

AC:

4712

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

1073

AN:

3472

East Asian (EAS)

AF:

0.358

AC:

1850

AN:

5170

South Asian (SAS)

AF:

0.216

AC:

1042

AN:

4822

European-Finnish (FIN)

AF:

0.259

AC:

2736

AN:

10554

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.302

AC:

20552

AN:

67980

Other (OTH)

AF:

0.346

AC:

729

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1718

3436

5153

6871

8589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<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:

0.317

Hom.:

26791

Bravo

AF:

0.357

TwinsUK

AF:

0.302

AC:

1121

ALSPAC

AF:

0.297

AC:

1144

ESP6500AA

AF:

0.470

AC:

2069

ESP6500EA

AF:

0.307

AC:

2637

ExAC

AF:

0.299

AC:

36362

Asia WGS

AF:

0.341

AC:

1185

AN:

3478

EpiCase

AF:

0.302

EpiControl

AF:

0.308

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lissencephaly 9 with complex brainstem malformation

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MACF1-related disorder

Benign:1

Jun 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.032

T;T;.;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.037

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.086

T;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

1.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

1.7

N;N;N;N;N

REVEL

Benign

0.077

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

.;.;T;.;.

Polyphen

0.0

.;B;.;.;.

Vest4

0.033

ClinPred

0.0046

GERP RS

5.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.019

gMVP

0.063

Mutation Taster

=100/0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over