Genetic Variant MACF1:p.Arg24_Ser25insSerCysArgSerGluArg (chr1-39084257-A-ATGTCGGAGTGAGCGGTCT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_012090.5(MACF1):c.54_71dupGTCTTGTCGGAGTGAGCG(p.Arg24_Ser25insSerCysArgSerGluArg) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000158 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

MACF1
NM_012090.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.15

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_012090.5.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5 link	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 1 of 93		NP_036222.3	Q9UPN3-2Q6ZSD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
MACF1	ENST00000567887.5 link	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 1 of 101	5	ENSP00000455823.1	H3BQK9
MACF1	ENST00000372915.8 link	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 1 of 96	5	ENSP00000362006.4	A0A7P0MQR8
MACF1	ENST00000361689.7 link	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 2 of 94	5	ENSP00000354573.2	Q9UPN3-2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

251130

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.0000935

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000167

AC:

244

AN:

1460624

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000615

Gnomad4 FIN exome

AF:

0.0000565

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000158

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.54_71dup, results in the insertion of 6 amino acid(s) of the MACF1 protein (p.Cys20_Ser25dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758220322, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MACF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2186705). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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