1-39084245-CAGTGAGCGGTCATGTCGG-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG

Variant names:

• chr1-39084245-C-CAGTGAGCGGTCATGTCGG
• rs545520541
• ENST00000567887.5:c.39_56dupATGTCGGAGTGAGCGGTC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_012090.5(MACF1):​c.39_56dupATGTCGGAGTGAGCGGTC​(p.Ser19_Cys20insCysArgSerGluArgSer) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000604 in 152,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MACF1 NM_012090.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.44

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 Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_012090.5.
• BP6: Variant 1-39084245-C-CAGTGAGCGGTCATGTCGG is Benign according to our data. Variant chr1-39084245-C-CAGTGAGCGGTCATGTCGG is described in ClinVar as [Likely_benign]. Clinvar id is 2848268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000604 (92/152292) while in subpopulation SAS AF= 0.00207 (10/4828). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5	c.39_56dupATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSer	disruptive_inframe_insertion	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_56dupATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSer	disruptive_inframe_insertion	Exon 1 of 101	5		ENSP00000455823.1
MACF1	ENST00000372915.8	c.39_56dupATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSer	disruptive_inframe_insertion	Exon 1 of 96	5		ENSP00000362006.4
MACF1	ENST00000361689.7	c.39_56dupATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSer	disruptive_inframe_insertion	Exon 2 of 94	5		ENSP00000354573.2

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000438 AC: 110 AN: 250904 Hom.: 0 AF XY: 0.000428 AC XY: 58 AN XY: 135670

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000490

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000350 AC: 511 AN: 1460924 Hom.: 2 Cov.: 30 AF XY: 0.000377 AC XY: 274 AN XY: 726814

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74476

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 24, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MACF1-related disorder Benign:1

Jan 26, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;