Variant 1-39448691-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001394062.1(MACF1):c.20186G>T(p.Ser6729Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6729T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

MACF1
NM_001394062.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.791

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.15156758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACF1	NM_001394062.1 linkuse as main transcript	c.20186G>T	p.Ser6729Ile	missense_variant	84/101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5 linkuse as main transcript	c.14009G>T	p.Ser4670Ile	missense_variant	79/93		NP_036222.3	Q9UPN3-2Q6ZSD7
MACF1	NM_001397473.1 linkuse as main transcript	c.8264G>T	p.Ser2755Ile	missense_variant	27/41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6 linkuse as main transcript	c.20186G>T	p.Ser6729Ile	missense_variant	84/101	5	NM_001394062.1	ENSP00000455274.1		H3BPE1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.13

T;T;.;T;.

Eigen

Benign

-0.092

Eigen_PC

Benign

0.040

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.39

T;T;T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.058

T;D;D;T;D

Sift4G

Uncertain

0.041

.;.;D;.;.

Polyphen

0.019

.;B;.;.;.

Vest4

0.16

MutPred

0.44

.;Loss of disorder (P = 0.0124);.;.;.;

MVP

0.28

ClinPred

0.77

GERP RS

5.3

Varity_R

0.070

gMVP

0.66

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