Genetic Variant MACF1:p.Ser19_Cys20insCysArgSerGluArgSerCysArgSerGluArgSer (chr1-39084245-C-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM4BP6_ModerateBS1BS2

The NM_012090.5(MACF1):c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC(p.Ser19_Cys20insCysArgSerGluArgSerCysArgSerGluArgSer) variant causes a disruptive 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
NM_012090.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.44

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_012090.5.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5 link	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSerCysArgSerGluArgSer	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.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSerCysArgSerGluArgSer	disruptive_inframe_insertion	Exon 1 of 101	5	ENSP00000455823.1	H3BQK9
MACF1	ENST00000372915.8 link	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSerCysArgSerGluArgSer	disruptive_inframe_insertion	Exon 1 of 96	5	ENSP00000362006.4	A0A7P0MQR8
MACF1	ENST00000361689.7 link	c.56_57insATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTC	p.Ser19_Cys20insCysArgSerGluArgSerCysArgSerGluArgSer	disruptive_inframe_insertion	Exon 2 of 94	5	ENSP00000354573.2	Q9UPN3-2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000749

AC:

188

AN:

250904

AF XY:

0.000545

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33470

Gnomad4 AMR exome

AF:

0.00381

AC:

170

AN:

44662

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86184

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52868

Gnomad4 NFE exome

AF:

8.99e-7

AC:

AN:

1111768

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60368

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000784

AC:

0.000784416

AN:

0.000784416

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=56/44

polymorphism

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