rs16826069

chr1-39331383-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_001394062.1(MACF1):c.4795A>G(p.Ile1599Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,782 control chromosomes in the GnomAD database, including 37,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2824 hom., cov: 31)
  • Exomes 𝑓: 0.21 (34444 hom.)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980

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 -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MACF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036052167).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACF1	NM_001394062.1	c.4795A>G	p.Ile1599Val	missense_variant	37/101	ENST00000564288.6
MACF1	NM_012090.5	c.4629+4030A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACF1	ENST00000564288.6	c.4795A>G	p.Ile1599Val	missense_variant	37/101	5	NM_001394062.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26125 AN: 151846 Hom.: 2826 Cov.: 31

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.219 AC: 55044 AN: 251250 Hom.: 6597 AF XY: 0.217 AC XY: 29490 AN XY: 135786

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.184

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.213 AC: 311365 AN: 1461816 Hom.: 34444 Cov.: 49 AF XY: 0.212 AC XY: 154338 AN XY: 727216

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.286

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.282

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.172 AC: 26117 AN: 151966 Hom.: 2824 Cov.: 31 AF XY: 0.171 AC XY: 12729 AN XY: 74254

Gnomad4 AFR AF: 0.0416

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.184

Alfa AF: 0.212 Hom.: 7670

Bravo AF: 0.170

TwinsUK AF: 0.212 AC: 787

ALSPAC AF: 0.207 AC: 799

ESP6500AA AF: 0.0463 AC: 204

ESP6500EA AF: 0.226 AC: 1945

ExAC AF: 0.212 AC: 25773

Asia WGS AF: 0.211 AC: 732 AN: 3478

EpiCase AF: 0.215

EpiControl AF: 0.221

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Benign	0.45
DEOGEN2	Benign	0.031	T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.75	T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.16	N;N;N;N
Sift	Benign	0.14	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.036
ClinPred		0.0015	T
GERP RS		-7.8
Varity_R		0.019

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: rs16826069; hg19: chr1-39797055; COSMIC: COSV57119077; COSMIC: COSV57119077;