1-39084245-C-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BS1 BS2

The ENST00000567887.5(MACF1):c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC(p.Cys14_Ser25dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0000788 in 152,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MACF1 ENST00000567887.5 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000567887.5.
• BP6: Variant 1-39084245-C-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG is Benign according to our data. Variant chr1-39084245-C-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG is described in ClinVar as [Benign]. Clinvar id is 2053003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000788 (12/152292) while in subpopulation AMR AF= 0.000784 (12/15298). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACF1	NM_012090.5	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Cys14_Ser25dup	inframe_insertion	1/93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACF1	ENST00000361689.7	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Cys14_Ser25dup	inframe_insertion	2/94	5
MACF1	ENST00000372915.8	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Cys14_Ser25dup	inframe_insertion	1/96	5		P1
MACF1	ENST00000484793.5	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Cys14_Ser25dup	inframe_insertion	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000749 AC: 188 AN: 250904 Hom.: 2 AF XY: 0.000545 AC XY: 74 AN XY: 135670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000119 AC: 174 AN: 1460922 Hom.: 2 Cov.: 30 AF XY: 0.0000922 AC XY: 67 AN XY: 726812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00381

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

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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;