1-39442834-G-A

Position:

chr1-39442834-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 12/19 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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=0.0015339851).

BP6

Variant 1-39442834-G-A is Benign according to our data. Variant chr1-39442834-G-A is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
MACF1	NM_001394062.1 linkuse as main transcript	c.19225G>A	p.Ala6409Thr	missense_variant	78/101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5 linkuse as main transcript	c.13048G>A	p.Ala4350Thr	missense_variant	73/93		NP_036222.3	Q9UPN3-2Q6ZSD7
MACF1	NM_001397473.1 linkuse as main transcript	c.7303G>A	p.Ala2435Thr	missense_variant	21/41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6 linkuse as main transcript	c.19225G>A	p.Ala6409Thr	missense_variant	78/101	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

GnomAD3 exomes

AF:

0.300

AC:

75074

AN:

250478

Hom.:

11475

AF XY:

0.292

AC XY:

39577

AN XY:

135382

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 SAS exome

AF:

0.215

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

Gnomad4 AFR exome

AF:

0.478

Gnomad4 AMR exome

AF:

0.287

Gnomad4 ASJ exome

AF:

0.309

Gnomad4 EAS exome

AF:

0.325

Gnomad4 SAS exome

AF:

0.214

Gnomad4 FIN exome

AF:

0.254

Gnomad4 NFE exome

AF:

0.301

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.346

AC:

52565

AN:

152042

Hom.:

9597

Cov.:

AF XY:

0.340

AC XY:

25252

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.472

Gnomad4 AMR

AF:

0.308

Gnomad4 ASJ

AF:

0.309

Gnomad4 EAS

AF:

0.358

Gnomad4 SAS

AF:

0.216

Gnomad4 FIN

AF:

0.259

Gnomad4 NFE

AF:

0.302

Gnomad4 OTH

AF:

0.346

Alfa

AF:

0.311

Hom.:

18221

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.052

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

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

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

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