1-39084253-G-A

Variant names:

• chr1-39084253-G-A
• rs200446050
• ENST00000567887.5:c.35G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_012090.5(MACF1):​c.35G>A​(p.Arg12Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: MACF1 NM_012090.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.25

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25979847).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000145 (22/152152) while in subpopulation NFE AF = 0.000265 (18/68006). AF 95% confidence interval is 0.000171. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5	c.35G>A	p.Arg12Gln	missense_variant	Exon 1 of 93		NP_036222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000567887.5	c.35G>A	p.Arg12Gln	missense_variant	Exon 1 of 101	5		ENSP00000455823.1
MACF1	ENST00000372915.8	c.35G>A	p.Arg12Gln	missense_variant	Exon 1 of 96	5		ENSP00000362006.4
MACF1	ENST00000361689.7	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 94	5		ENSP00000354573.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251092 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 354 AN: 1460536 Hom.: 0 Cov.: 30 AF XY: 0.000208 AC XY: 151 AN XY: 726652

Gnomad4 AFR exome AF: 0.0000597 AC: 2 AN: 33476

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44658

Gnomad4 ASJ exome AF: 0.000306 AC: 8 AN: 26136

Gnomad4 EAS exome AF: 0.000101 AC: 4 AN: 39694

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52970

Gnomad4 NFE exome AF: 0.000300 AC: 333 AN: 1111252

Gnomad4 Remaining exome AF: 0.000116 AC: 7 AN: 60334

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74334

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241406 AN: 0.0000241406

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654279 AN: 0.0000654279

Gnomad4 ASJ AF: 0.000288 AC: 0.000288184 AN: 0.000288184

Gnomad4 EAS AF: 0.000193 AC: 0.00019253 AN: 0.00019253

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000265 AC: 0.000264683 AN: 0.000264683

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lissencephaly 9 with complex brainstem malformation Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 26, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Benign:1

Oct 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.34	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D;.;N;N;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Uncertain	0.046	D;D;.;.;D
Vest4		0.50
MVP		0.68
ClinPred		0.58	D
GERP RS		5.3
Varity_R		0.40
gMVP		0.49
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs200446050; hg19: chr1-39549925; COSMIC: COSV58391228;