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

Variant summary

Our verdict is Benign. Variant got -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. 13/15 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.219

AC:

55044

AN:

251250

Hom.:

6597

AF XY:

0.217

AC XY:

29490

AN XY:

135786

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 SAS exome

AF:

0.184

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

Gnomad4 AFR exome

AF:

0.0349

Gnomad4 AMR exome

AF:

0.286

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.282

Gnomad4 SAS exome

AF:

0.183

Gnomad4 FIN exome

AF:

0.208

Gnomad4 NFE exome

AF:

0.216

Gnomad4 OTH exome

AF:

0.200

GnomAD4 genome

AF:

0.172

AC:

26117

AN:

151966

Hom.:

2824

Cov.:

AF XY:

0.171

AC XY:

12729

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0416

Gnomad4 AMR

AF:

0.223

Gnomad4 ASJ

AF:

0.229

Gnomad4 EAS

AF:

0.285

Gnomad4 SAS

AF:

0.182

Gnomad4 FIN

AF:

0.216

Gnomad4 NFE

AF:

0.221

Gnomad4 OTH

AF:

0.184

Alfa

AF:

0.212

Hom.:

7670

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over