1-39084257-ATGTCGGAGTGAGCGGTCT-ATGTCGGAGTGAGCGGTCTTGTCGGAGTGAGCGGTCT

Variant names:

• chr1-39084257-A-ATGTCGGAGTGAGCGGTCT
• rs376408478
• ENST00000567887.5:c.54_71dupGTCTTGTCGGAGTGAGCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_012090.5(MACF1):​c.54_71dupGTCTTGTCGGAGTGAGCG​(p.Arg24_Ser25insSerCysArgSerGluArg) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000158 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: MACF1 NM_012090.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15
• 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: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_012090.5.
• BS2: High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012090.5. 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_012090.5		c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 1 of 93	NP_036222.3	Q9UPN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000567887.5	TSL:5	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 1 of 101	ENSP00000455823.1	H3BQK9
	MACF1	ENST00000372915.8	TSL:5	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 1 of 96	ENSP00000362006.4	A0A7P0MQR8
	MACF1	ENST00000361689.7	TSL:5	c.54_71dupGTCTTGTCGGAGTGAGCG	p.Arg24_Ser25insSerCysArgSerGluArg	disruptive_inframe_insertion	Exon 2 of 94	ENSP00000354573.2	Q9UPN3-2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251130 AF XY: 0.000177

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000326

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000167 AC: 244 AN: 1460624 Hom.: 1 Cov.: 30 AF XY: 0.000180 AC XY: 131 AN XY: 726692

African (AFR) AF: 0.000209 AC: 7 AN: 33476

American (AMR) AF: 0.0000672 AC: 3 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86248

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1111246

Other (OTH) AF: 0.000249 AC: 15 AN: 60336

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74432

African (AFR) AF: 0.000168 AC: 7 AN: 41548

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=63/37	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs376408478; hg19: chr1-39549929;