1-39084257-A-ATGTCGGAGTGAGCGGTCT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The ENST00000567887.5(MACF1):c.54_71dup(p.Cys20_Ser25dup) variant causes a 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 ENST00000567887.5 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000567887.5.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACF1	NM_012090.5	c.54_71dup	p.Cys20_Ser25dup	inframe_insertion	1/93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACF1	ENST00000361689.7	c.54_71dup	p.Cys20_Ser25dup	inframe_insertion	2/94	5
MACF1	ENST00000372915.8	c.54_71dup	p.Cys20_Ser25dup	inframe_insertion	1/96	5		P1
MACF1	ENST00000484793.5	c.54_71dup	p.Cys20_Ser25dup	inframe_insertion	3/4	2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152106 Hom.: 0 Cov.: 32

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: 49 AN: 251130 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135770

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.: 1 Cov.: 30 AF XY: 0.000180 AC XY: 131 AN XY: 726692

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: 24 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74432

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376408478; hg19: chr1-39549929;