rs668556

chr1-39448691-G-Cchr1-39448691-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001394062.1(MACF1):c.20186G>C(p.Ser6729Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,611,318 control chromosomes in the GnomAD database, including 261,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29611 hom., cov: 31)
  • Exomes 𝑓: 0.56 (231523 hom.)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.791

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MACF1
• BP4: Computational evidence support a benign effect (MetaRNN=1.3418958E-6).
• BP6: Variant 1-39448691-G-C is Benign according to our data. Variant chr1-39448691-G-C is described in ClinVar as [Benign]. Clinvar id is 1277352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACF1	NM_001394062.1	c.20186G>C	p.Ser6729Thr	missense_variant	84/101	ENST00000564288.6
MACF1	NM_012090.5	c.14009G>C	p.Ser4670Thr	missense_variant	79/93
MACF1	NM_001397473.1	c.8264G>C	p.Ser2755Thr	missense_variant	27/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACF1	ENST00000564288.6	c.20186G>C	p.Ser6729Thr	missense_variant	84/101	5	NM_001394062.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92815 AN: 151848 Hom.: 29554 Cov.: 31

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.598

GnomAD3 exomes AF: 0.530 AC: 132953 AN: 250730 Hom.: 37190 AF XY: 0.524 AC XY: 70971 AN XY: 135556

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.621

Gnomad EAS exome AF: 0.349

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.549

GnomAD4 exome AF: 0.557 AC: 812514 AN: 1459352 Hom.: 231523 Cov.: 36 AF XY: 0.551 AC XY: 400112 AN XY: 725980

Gnomad4 AFR exome AF: 0.791

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.618

Gnomad4 EAS exome AF: 0.315

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.591

Gnomad4 NFE exome AF: 0.575

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.611 AC: 92926 AN: 151966 Hom.: 29611 Cov.: 31 AF XY: 0.603 AC XY: 44773 AN XY: 74258

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.612

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.600

Alfa AF: 0.565 Hom.: 17306

Bravo AF: 0.617

TwinsUK AF: 0.571 AC: 2118

ALSPAC AF: 0.570 AC: 2195

ESP6500AA AF: 0.771 AC: 3397

ESP6500EA AF: 0.580 AC: 4989

ExAC AF: 0.538 AC: 65313

Asia WGS AF: 0.413 AC: 1436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2020	- -

Lissencephaly 9 with complex brainstem malformation Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	21
Dann	Benign	0.23
DEOGEN2	Benign	0.043	T;T;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.080	T;T;T;T;T
MetaRNN	Benign	0.0000013	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.4	N;N;N;N;N
Sift	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;B;.;.;.
Vest4		0.047
ClinPred		0.0020	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.41

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: rs668556; hg19: chr1-39914363; COSMIC: COSV57122623; COSMIC: COSV57122623;