rs2296172

Positions:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP6_Very_StrongBA1

The NM_001394062.1(MACF1):c.13054A>G(p.Met4352Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,338 control chromosomes in the GnomAD database, including 33,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2441 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30663 hom. )

Consequence

MACF1
NM_001394062.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.409

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:

MACF1 (HGNC:):

MACF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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.

BP6

Variant 1-39370145-A-G is Benign according to our data. Variant chr1-39370145-A-G is described in ClinVar as [Benign]. Clinvar id is 1232730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACF1	NM_001394062.1 linkuse as main transcript	c.13054A>G	p.Met4352Val	missense_variant	51/101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5 linkuse as main transcript	c.6868A>G	p.Met2290Val	missense_variant	45/93		NP_036222.3	Q9UPN3-2Q6ZSD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6 linkuse as main transcript	c.13054A>G	p.Met4352Val	missense_variant	51/101	5	NM_001394062.1	ENSP00000455274.1		H3BPE1

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24334

AN:

152104

Hom.:

2441

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0399

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.188

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.177

GnomAD3 exomes

AF:

0.188

AC:

47236

AN:

250828

Hom.:

4821

AF XY:

0.186

AC XY:

25258

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.0375

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.177

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.183

GnomAD4 exome

AF:

0.200

AC:

292667

AN:

1461116

Hom.:

30663

Cov.:

AF XY:

0.198

AC XY:

144039

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.0331

Gnomad4 AMR exome

AF:

0.216

Gnomad4 ASJ exome

AF:

0.235

Gnomad4 EAS exome

AF:

0.167

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.197

Gnomad4 NFE exome

AF:

0.213

Gnomad4 OTH exome

AF:

0.184

GnomAD4 genome

AF:

0.160

AC:

24326

AN:

152222

Hom.:

2441

Cov.:

AF XY:

0.157

AC XY:

11690

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0398

Gnomad4 AMR

AF:

0.187

Gnomad4 ASJ

AF:

0.227

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.205

Gnomad4 NFE

AF:

0.219

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.206

Hom.:

8492

Bravo

AF:

0.156

TwinsUK

AF:

0.211

AC:

782

ALSPAC

AF:

0.206

AC:

793

ESP6500AA

AF:

0.0440

AC:

194

ESP6500EA

AF:

0.223

AC:

1919

ExAC

AF:

0.183

AC:

22265

Asia WGS

AF:

0.118

AC:

410

AN:

3478

EpiCase

AF:

0.213

EpiControl

AF:

0.218

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 29748316, 29632382, 23160641) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Lissencephaly 9 with complex brainstem malformation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

MACF1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

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

0.059

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.063

T;T;.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.77

T;T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

0.85

T;T;T;T;T

Sift4G

Benign

0.24

.;.;T;.;.

Polyphen

0.0

.;B;B;.;.

Vest4

0.039

ClinPred

0.0055

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.63

Position offset: -1

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