17-4948563-T-TCCCCCCCCCC

Variant names:

• chr17-4948563-T-TCCCCCCCCCC
• rs376068871
• ENST00000896245.1:c.-3+199_-3+200insCCCCCCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000572383.1(PFN1):​c.77-9_77-8insGGGGGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000817 in 122,422 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000082 (0 hom., cov: 28)
• Consequence: PFN1 ENST00000572383.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 1 publications found

Genes affected

ENO3 (HGNC:3354): (enolase 3) This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme is found in skeletal muscle cells in the adult where it may play a role in muscle development and regeneration. A switch from alpha enolase to beta enolase occurs in muscle tissue during development in rodents. Mutations in this gene have be associated glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jul 2010]

PFN1 (HGNC:8881): (profilin 1) This gene encodes a member of the profilin family of small actin-binding proteins. The encoded protein plays an important role in actin dynamics by regulating actin polymerization in response to extracellular signals. Deletion of this gene is associated with Miller-Dieker syndrome, and the encoded protein may also play a role in Huntington disease. Multiple pseudogenes of this gene are located on chromosome 1. [provided by RefSeq, Jul 2012]

PFN1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000572383.1. 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
	PFN1	NM_005022.4	MANE Select	c.-170_-169insGGGGGGGGGG		upstream_gene	N/A	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-170_-169insGGGGGGGGGG		upstream_gene	N/A	NP_001362920.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENO3	ENST00000896245.1		c.-3+199_-3+200insCCCCCCCCCC		intron	N/A	ENSP00000566304.1
	ENO3	ENST00000520221.5	TSL:5	c.-3+190_-3+191insCCCCCCCCCC		intron	N/A	ENSP00000467444.1	K7EPM1
	PFN1	ENST00000572383.1	TSL:3	c.77-9_77-8insGGGGGGGGGG		intron	N/A	ENSP00000460363.1	I3L3D5

Frequencies

GnomAD3 genomes AF: 0.00000817 AC: 1 AN: 122422 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 3

GnomAD4 genome AF: 0.00000817 AC: 1 AN: 122422 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 59198

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

African (AFR) AF: 0.0000322 AC: 1 AN: 31064

American (AMR) AF: 0.00 AC: 0 AN: 12238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2972

East Asian (EAS) AF: 0.00 AC: 0 AN: 4180

South Asian (SAS) AF: 0.00 AC: 0 AN: 3688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57842

Other (OTH) AF: 0.00 AC: 0 AN: 1614

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs376068871; hg19: chr17-4851858;