17-4948563-TCCC-TCCCCCCCC

Variant names:

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

Variant summary

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

The ENST00000572383.1(PFN1):​c.77-9_77-8insGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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_-169insGGGGG		upstream_gene	N/A	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-170_-169insGGGGG		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+200insCCCCC		intron	N/A	ENSP00000566304.1
	ENO3	ENST00000520221.5	TSL:5	c.-3+190_-3+191insCCCCC		intron	N/A	ENSP00000467444.1	K7EPM1
	PFN1	ENST00000572383.1	TSL:3	c.77-9_77-8insGGGGG		intron	N/A	ENSP00000460363.1	I3L3D5

Frequencies

GnomAD3 genomes AF: 0.000596 AC: 73 AN: 122394 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000354

Gnomad AMI AF: 0.00124

Gnomad AMR AF: 0.000572

Gnomad ASJ AF: 0.00168

Gnomad EAS AF: 0.000478

Gnomad SAS AF: 0.00163

Gnomad FIN AF: 0.000386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000657

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000293 AC: 1 AN: 341138 Hom.: 0 Cov.: 3 AF XY: 0.00000570 AC XY: 1 AN XY: 175538

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

African (AFR) AF: 0.00 AC: 0 AN: 6878

American (AMR) AF: 0.00 AC: 0 AN: 6380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8938

East Asian (EAS) AF: 0.00 AC: 0 AN: 19394

South Asian (SAS) AF: 0.00 AC: 0 AN: 22078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1432

European-Non Finnish (NFE) AF: 0.00000424 AC: 1 AN: 235616

Other (OTH) AF: 0.00 AC: 0 AN: 18510

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000596 AC: 73 AN: 122424 Hom.: 0 Cov.: 28 AF XY: 0.000388 AC XY: 23 AN XY: 59232

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

African (AFR) AF: 0.000353 AC: 11 AN: 31128

American (AMR) AF: 0.000571 AC: 7 AN: 12250

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 5 AN: 2972

East Asian (EAS) AF: 0.000480 AC: 2 AN: 4170

South Asian (SAS) AF: 0.00163 AC: 6 AN: 3670

European-Finnish (FIN) AF: 0.000386 AC: 3 AN: 7762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.000657 AC: 38 AN: 57816

Other (OTH) AF: 0.00 AC: 0 AN: 1622

⚠️ 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.

Alfa AF: 0.000148 Hom.: 36

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;