rs193920778

Variant names:

• chr1-39370027-CAGAG-C
• rs193920778
• NM_001394062.1:c.12940_12943delGAGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP3_Moderate

The NM_001394062.1(MACF1):​c.12940_12943delGAGA​(p.Glu4314fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACF1 NM_001394062.1 frameshift, splice_region
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.22
• Publications: 0 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), Ambry Genetics, Orphanet
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	NM_001394062.1	MANE Select	c.12940_12943delGAGA	p.Glu4314fs	frameshift splice_region	Exon 51 of 101	NP_001380991.1	H3BPE1
	MACF1	NM_012090.5		c.6754_6757delGAGA	p.Glu2252fs	frameshift splice_region	Exon 45 of 93	NP_036222.3	Q9UPN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000564288.6	TSL:5 MANE Select	c.12939-2_12940delAGAG	p.Lys4315fs	frameshift splice_acceptor splice_region intron	Exon 51 of 101	ENSP00000455274.1	H3BPE1
	MACF1	ENST00000567887.5	TSL:5	c.13050-2_13051delAGAG	p.Lys4352fs	frameshift splice_acceptor splice_region intron	Exon 51 of 101	ENSP00000455823.1	H3BQK9
	MACF1	ENST00000372915.8	TSL:5	c.12954-2_12955delAGAG	p.Lys4320fs	frameshift splice_acceptor splice_region intron	Exon 50 of 96	ENSP00000362006.4	A0A7P0MQR8

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 7
DS_AL_spliceai		1.0		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193920778; hg19: chr1-39835699; COSMIC: COSV57150171;