chr1-39448691-G-C

Variant names:

• chr1-39448691-G-C
• rs668556
• NM_001394062.1:c.20186G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/20 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
• Publications: 43 publications found

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 Gene-Disease associations (from GenCC):

• lissencephaly 9 with complex brainstem malformation

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics
• lissencephaly spectrum disorder with complex brainstem malformation

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 rank	MANE	Protein	UniProt
MACF1	NM_001394062.1	c.20186G>C	p.Ser6729Thr	missense_variant	Exon 84 of 101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5	c.14009G>C	p.Ser4670Thr	missense_variant	Exon 79 of 93		NP_036222.3
MACF1	NM_001397473.1	c.8264G>C	p.Ser2755Thr	missense_variant	Exon 27 of 41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6	c.20186G>C	p.Ser6729Thr	missense_variant	Exon 84 of 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

GnomAD2 exomes AF: 0.530 AC: 132953 AN: 250730 AF XY: 0.524

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 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

African (AFR) AF: 0.791 AC: 26442 AN: 33432

American (AMR) AF: 0.431 AC: 19223 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 16098 AN: 26066

East Asian (EAS) AF: 0.315 AC: 12490 AN: 39646

South Asian (SAS) AF: 0.366 AC: 31464 AN: 85854

European-Finnish (FIN) AF: 0.591 AC: 31500 AN: 53288

Middle Eastern (MID) AF: 0.598 AC: 3444 AN: 5756

European-Non Finnish (NFE) AF: 0.575 AC: 638497 AN: 1110470

Other (OTH) AF: 0.553 AC: 33356 AN: 60286

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

African (AFR) AF: 0.782 AC: 32402 AN: 41448

American (AMR) AF: 0.499 AC: 7626 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2122 AN: 3470

East Asian (EAS) AF: 0.349 AC: 1801 AN: 5164

South Asian (SAS) AF: 0.350 AC: 1685 AN: 4816

European-Finnish (FIN) AF: 0.586 AC: 6173 AN: 10530

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39093 AN: 67958

Other (OTH) AF: 0.600 AC: 1261 AN: 2102

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lissencephaly 9 with complex brainstem malformation Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.79
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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