Genetic Variant MACF1:p.Arg12Trp (chr1-39084252-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_012090.5(MACF1):c.34C>T(p.Arg12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

MACF1
NM_012090.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.548

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant 1-39084252-C-T is Benign according to our data. Variant chr1-39084252-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3709041.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000263 (4/152246) while in subpopulation EAS AF= 0.000579 (3/5184). AF 95% confidence interval is 0.000157. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5 link	c.34C>T	p.Arg12Trp	missense_variant	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.34C>T	p.Arg12Trp	missense_variant	Exon 1 of 101	5	ENSP00000455823.1	H3BQK9
MACF1	ENST00000372915.8 link	c.34C>T	p.Arg12Trp	missense_variant	Exon 1 of 96	5	ENSP00000362006.4	A0A7P0MQR8
MACF1	ENST00000361689.7 link	c.34C>T	p.Arg12Trp	missense_variant	Exon 2 of 94	5	ENSP00000354573.2	Q9UPN3-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

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:

0.0000159

AC:

AN:

250986

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460470

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T;D;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

.;D;D;D;D

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.48

T;T;T;T;T

MetaSVM

Benign

-0.53

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.8

D;.;D;D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Uncertain

0.0050

D;D;.;.;D

Vest4

0.68

MVP

0.73

ClinPred

0.99

GERP RS

4.4

Varity_R

0.27

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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