chr1-39084253-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The ENST00000567887.5(MACF1):c.35G>A(p.Arg12Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
MACF1
ENST00000567887.5 missense
ENST00000567887.5 missense
Scores
2
7
8
Clinical Significance
Conservation
PhyloP100: 7.25
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MACF1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.25979847).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000145 (22/152152) while in subpopulation NFE AF= 0.000265 (18/68006). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MACF1 | NM_012090.5 | c.35G>A | p.Arg12Gln | missense_variant | 1/93 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MACF1 | ENST00000567887.5 | c.35G>A | p.Arg12Gln | missense_variant | 1/101 | 5 | |||
MACF1 | ENST00000372915.8 | c.35G>A | p.Arg12Gln | missense_variant | 1/96 | 5 | P1 | ||
MACF1 | ENST00000361689.7 | c.35G>A | p.Arg12Gln | missense_variant | 2/94 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000139 AC: 35AN: 251092Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135762
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GnomAD4 exome AF: 0.000242 AC: 354AN: 1460536Hom.: 0 Cov.: 30 AF XY: 0.000208 AC XY: 151AN XY: 726652
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Lissencephaly 9 with complex brainstem malformation Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 28, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;N;N;N
REVEL
Benign
Sift
Pathogenic
D;.;D;D;D
Sift4G
Uncertain
D;D;.;.;D
Vest4
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at