rs12118033

Variant names:

• chr1-39092539-G-A
• rs12118033
• ENST00000567887.5:c.220+8101G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000567887.5(MACF1):​c.220+8101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 152,136 control chromosomes in the GnomAD database, including 527 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.077 (527 hom., cov: 32)
• Consequence: MACF1 ENST00000567887.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.93
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5	c.220+8101G>A		intron_variant	Intron 1 of 92		NP_036222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000567887.5	c.220+8101G>A		intron_variant	Intron 1 of 100	5		ENSP00000455823.1
MACF1	ENST00000372915.8	c.220+8101G>A		intron_variant	Intron 1 of 95	5		ENSP00000362006.4
MACF1	ENST00000361689.7	c.220+8101G>A		intron_variant	Intron 2 of 93	5		ENSP00000354573.2

Frequencies

GnomAD3 genomes AF: 0.0770 AC: 11699 AN: 152018 Hom.: 523 Cov.: 32

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0934

Gnomad OTH AF: 0.0760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0770 AC: 11721 AN: 152136 Hom.: 527 Cov.: 32 AF XY: 0.0783 AC XY: 5824 AN XY: 74358

African (AFR) AF: 0.0540 AC: 2243 AN: 41502

American (AMR) AF: 0.0577 AC: 882 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0382 AC: 184 AN: 4816

European-Finnish (FIN) AF: 0.156 AC: 1649 AN: 10584

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0934 AC: 6353 AN: 67984

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0857 Hom.: 451

Bravo AF: 0.0701

Asia WGS AF: 0.0290 AC: 103 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.69
DANN	Benign	0.48
PhyloP100		-2.9
Mutation Taster		=100/0	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: rs12118033; hg19: chr1-39558211;