rs545520541

Variant names:

• chr1-39084245-CAGTGAGCGGTCATGTCGG-C
• rs545520541
• ENST00000567887.5:c.39_56delATGTCGGAGTGAGCGGTC

Your query was ambiguous. Multiple possible variants found:

• chr1-39084245-CAGTGAGCGGTCATGTCGG-C
• chr1-39084245-CAGTGAGCGGTCATGTCGG-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG
• chr1-39084245-CAGTGAGCGGTCATGTCGG-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM4 PP3 BS1_Supporting BS2

The NM_012090.5(MACF1):​c.39_56delATGTCGGAGTGAGCGGTC​(p.Cys14_Ser19del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,202 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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: 0.00030 (1 hom.)
• Consequence: MACF1 NM_012090.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.03
• 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: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_012090.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000164 (25/152292) while in subpopulation NFE AF = 0.000265 (18/68012). AF 95% confidence interval is 0.000171. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 25 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.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	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.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 1 of 101	ENSP00000455823.1	H3BQK9
	MACF1	ENST00000372915.8	TSL:5	c.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 1 of 96	ENSP00000362006.4	A0A7P0MQR8
	MACF1	ENST00000361689.7	TSL:5	c.39_56delATGTCGGAGTGAGCGGTC	p.Cys14_Ser19del	disruptive_inframe_deletion	Exon 2 of 94	ENSP00000354573.2	Q9UPN3-2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000265

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 250904 AF XY: 0.000214

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000298 AC: 436 AN: 1460910 Hom.: 1 AF XY: 0.000279 AC XY: 203 AN XY: 726810

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

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.000716 AC: 32 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86184

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52868

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

European-Non Finnish (NFE) AF: 0.000329 AC: 366 AN: 1111756

Other (OTH) AF: 0.000447 AC: 27 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74476

African (AFR) AF: 0.0000962 AC: 4 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68012

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000109 Hom.: 0

ClinVar

ClinVar submissions

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		9.0
Mutation Taster		=101/99	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs545520541; hg19: chr1-39549917;