rs661316

Variant names:

• chr1-39165625-G-A
• rs661316
• ENST00000567887.5:c.221-65557G>A

Variant summary

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

The ENST00000567887.5(MACF1):​c.221-65557G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 151,996 control chromosomes in the GnomAD database, including 6,596 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 0.29 (6596 hom., cov: 32)
• Consequence: MACF1 ENST00000567887.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.254
• Publications: 8 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 (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5	c.221-65557G>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.221-65557G>A		intron_variant	Intron 1 of 100	5		ENSP00000455823.1
MACF1	ENST00000372915.8	c.221-65557G>A		intron_variant	Intron 1 of 95	5		ENSP00000362006.4
MACF1	ENST00000361689.7	c.221-65557G>A		intron_variant	Intron 2 of 93	5		ENSP00000354573.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43702 AN: 151878 Hom.: 6575 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.287

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

GnomAD4 genome AF: 0.288 AC: 43770 AN: 151996 Hom.: 6596 Cov.: 32 AF XY: 0.283 AC XY: 20988 AN XY: 74290

African (AFR) AF: 0.373 AC: 15435 AN: 41426

American (AMR) AF: 0.266 AC: 4060 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3468

East Asian (EAS) AF: 0.331 AC: 1714 AN: 5184

South Asian (SAS) AF: 0.157 AC: 757 AN: 4814

European-Finnish (FIN) AF: 0.219 AC: 2311 AN: 10562

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17669 AN: 67954

Other (OTH) AF: 0.292 AC: 617 AN: 2112

Alfa AF: 0.275 Hom.: 919

Bravo AF: 0.297

Asia WGS AF: 0.296 AC: 1028 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	1.1
DANN	Benign	0.33
PhyloP100		-0.25
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: rs661316; hg19: chr1-39631297;