rs138819868

Positions:

chr1-39485632-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001394062.1(MACF1):c.22506T>G(p.Phe7502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,186 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 16 hom. )

Consequence

MACF1
NM_001394062.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.0620

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MACF1. . Gene score misZ 0.58309 (greater than the threshold 3.09). Trascript score misZ 6.1868 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly spectrum disorder with complex brainstem malformation, lissencephaly 9 with complex brainstem malformation.

BP4

Computational evidence support a benign effect (MetaRNN=0.006961316).

BP6

Variant 1-39485632-T-G is Benign according to our data. Variant chr1-39485632-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438598.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr1-39485632-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00282 (429/152310) while in subpopulation NFE AF= 0.00453 (308/68030). AF 95% confidence interval is 0.00411. There are 1 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MACF1	NM_001394062.1 linkuse as main transcript	c.22506T>G	p.Phe7502Leu	missense_variant	101/101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5 linkuse as main transcript	c.16131T>G	p.Phe5377Leu	missense_variant	93/93		NP_036222.3
MACF1	NM_001397473.1 linkuse as main transcript	c.10386T>G	p.Phe3462Leu	missense_variant	41/41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6 linkuse as main transcript	c.22506T>G	p.Phe7502Leu	missense_variant	101/101	5	NM_001394062.1	ENSP00000455274

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

429

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00225

AC:

566

AN:

251426

Hom.:

AF XY:

0.00247

AC XY:

336

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00403

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00383

AC:

5601

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

2723

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00247

Gnomad4 NFE exome

AF:

0.00466

Gnomad4 OTH exome

AF:

0.00328

GnomAD4 genome

AF:

0.00282

AC:

429

AN:

152310

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00392

Hom.:

Bravo

AF:

0.00296

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00245

AC:

298

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MACF1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	- -

Abnormal corpus callosum morphology

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 01, 2017

this variant was indentified in an individual with malformations of cortical development -

MACF1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

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

Pathogenic

0.97

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;D;.;T;.

Eigen

Benign

0.046

Eigen_PC

Benign

0.064

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.0070

T;T;T;T;T

MetaSVM

Benign

-0.74

MutationTaster

Benign

0.98

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.2

D;D;D;D;D

REVEL

Uncertain

0.29

Sift

Benign

0.070

T;T;T;T;T

Sift4G

Uncertain

0.0020

.;.;D;.;.

Polyphen

0.89

.;P;.;.;.

Vest4

0.42

MutPred

0.17

.;Gain of loop (P = 0.0502);.;.;.;

MVP

0.68

ClinPred

0.063

GERP RS

4.5

Varity_R

0.32

gMVP

0.19

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over