rs545520541

Variant names:

• chr1-39084245-CAGTGAGCGGTCATGTCGG-C
• rs545520541
• ENST00000567887.5:c.39_56delATGTCGGAGTGAGCGGTC

Your query was ambiguous. Multiple possible variants found:

• chr1-39084245-CAGTGAGCGGTCATGTCGG-C
• chr1-39084245-CAGTGAGCGGTCATGTCGG-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG
• chr1-39084245-CAGTGAGCGGTCATGTCGG-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM4 PP3 BS1_Supporting BS2

The NM_012090.5(MACF1):​c.39_56delATGTCGGAGTGAGCGGTC​(p.Cys14_Ser19del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,202 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: MACF1 NM_012090.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.03

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 NM_012090.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000164 (25/152292) while in subpopulation NFE AF= 0.000265 (18/68012). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 12 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 GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5	c.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 1 of 93		NP_036222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000567887.5	c.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 1 of 101	5		ENSP00000455823.1
MACF1	ENST00000372915.8	c.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 1 of 96	5		ENSP00000362006.4
MACF1	ENST00000361689.7	c.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 2 of 94	5		ENSP00000354573.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000265

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 250904 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135670

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000298 AC: 436 AN: 1460910 Hom.: 1 AF XY: 0.000279 AC XY: 203 AN XY: 726810

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74476

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000109 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.39_56del, results in the deletion of 6 amino acid(s) of the MACF1 protein (p.Cys20_Ser25del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750221568, gnomAD 0.06%), 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: 2085771). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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: rs545520541; hg19: chr1-39549917;