rs668556

Positions:

• chr1-39448691-G-C
• chr1-39448691-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. 14/19 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:4
• 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]

MACF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MACF1. . Gene score misZ 0.58309 (greater than the threshold 3.09). Trascript score misZ 6.1868 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly spectrum disorder with complex brainstem malformation, lissencephaly 9 with complex brainstem malformation.
• 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	Protein	UniProt
MACF1	NM_001394062.1	c.20186G>C	p.Ser6729Thr	missense_variant	84/101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5	c.14009G>C	p.Ser4670Thr	missense_variant	79/93		NP_036222.3
MACF1	NM_001397473.1	c.8264G>C	p.Ser2755Thr	missense_variant	27/41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6	c.20186G>C	p.Ser6729Thr	missense_variant	84/101	5	NM_001394062.1	ENSP00000455274.1

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.4	N;N;N;N;N
REVEL	Benign	0.085
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	.;.;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;