NM_001394062.1:c.20186G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394062.1(MACF1):​c.20186G>T​(p.Ser6729Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6729T) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15156758).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394062.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	NM_001394062.1	MANE Select	c.20186G>T	p.Ser6729Ile	missense	Exon 84 of 101	NP_001380991.1
	MACF1	NM_012090.5		c.14009G>T	p.Ser4670Ile	missense	Exon 79 of 93	NP_036222.3
	MACF1	NM_001397473.1		c.8264G>T	p.Ser2755Ile	missense	Exon 27 of 41	NP_001384402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000564288.6	TSL:5 MANE Select	c.20186G>T	p.Ser6729Ile	missense	Exon 84 of 101	ENSP00000455274.1
	MACF1	ENST00000567887.5	TSL:5	c.20297G>T	p.Ser6766Ile	missense	Exon 84 of 101	ENSP00000455823.1
	MACF1	ENST00000372915.8	TSL:5	c.19874G>T	p.Ser6625Ile	missense	Exon 82 of 96	ENSP00000362006.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74178

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 17306

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.79
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.058	T
Sift4G	Uncertain	0.041	D
Polyphen		0.019	B
Vest4		0.16
MutPred		0.44		Loss of disorder (P = 0.0124)
MVP		0.28
ClinPred		0.77	D
GERP RS		5.3
Varity_R		0.070
gMVP		0.66
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs668556; hg19: chr1-39914363;