chr1-39084270-C-T

Position:

chr1-39084270-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2

The ENST00000567887.5(MACF1):c.52C>T(p.Arg18Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MACF1
ENST00000567887.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0740

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 Likely_benign. Variant got -4 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 6.2367 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly spectrum disorder with complex brainstem malformation, lissencephaly 9 with complex brainstem malformation.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000142 (207/1461338) while in subpopulation NFE AF= 0.000176 (196/1111876). AF 95% confidence interval is 0.000156. There are 0 homozygotes in gnomad4_exome. There are 92 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACF1	NM_012090.5 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant	1/93		NP_036222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	Appris	UniProt
MACF1	ENST00000567887.5 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant	1/101	5	ENSP00000455823
MACF1	ENST00000372915.8 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant	1/96	5	ENSP00000362006	P1
MACF1	ENST00000361689.7 linkuse as main transcript	c.52C>T	p.Arg18Trp	missense_variant	2/94	5	ENSP00000354573		Q9UPN3-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251208

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461338

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000176

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000112

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2023

This variant is present in population databases (rs369843705, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 18 of the MACF1 protein (p.Arg18Trp). This variant has not been reported in the literature in individuals affected with MACF1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T;T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.45

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationTaster

Benign

0.75

N;N;N;N;N;N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.0

D;.;D;N;D

REVEL

Benign

0.23

Sift

Uncertain

0.0070

D;.;D;D;D

Sift4G

Uncertain

0.025

D;D;.;.;D

Vest4

0.66

MVP

0.60

ClinPred

0.75

GERP RS

0.69

Varity_R

0.11

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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