17-4948563-TCC-T

Variant names:

• chr17-4948563-TCC-T
• rs376068871
• ENST00000896245.1:c.-3+200_-3+201delCC

Variant summary

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

The ENST00000572383.1(PFN1):​c.77-10_77-9delGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 462,512 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00030 (0 hom.)
• 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 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.-171_-170delGG		upstream_gene	N/A	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-171_-170delGG		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+200_-3+201delCC		intron	N/A	ENSP00000566304.1
	ENO3	ENST00000520221.5	TSL:5	c.-3+191_-3+192delCC		intron	N/A	ENSP00000467444.1	K7EPM1
	PFN1	ENST00000572383.1	TSL:3	c.77-10_77-9delGG		intron	N/A	ENSP00000460363.1	I3L3D5

Frequencies

GnomAD3 genomes AF: 0.0000163 AC: 2 AN: 122416 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000817

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

GnomAD2 exomes AF: 0.00215 AC: 2 AN: 932 AF XY: 0.00185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000297 AC: 101 AN: 340096 Hom.: 0 AF XY: 0.000320 AC XY: 56 AN XY: 174980

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

African (AFR) AF: 0.000146 AC: 1 AN: 6866

American (AMR) AF: 0.00 AC: 0 AN: 6360

Ashkenazi Jewish (ASJ) AF: 0.000112 AC: 1 AN: 8904

East Asian (EAS) AF: 0.0000517 AC: 1 AN: 19360

South Asian (SAS) AF: 0.000227 AC: 5 AN: 21994

European-Finnish (FIN) AF: 0.0000458 AC: 1 AN: 21822

Middle Eastern (MID) AF: 0.000703 AC: 1 AN: 1422

European-Non Finnish (NFE) AF: 0.000362 AC: 85 AN: 234902

Other (OTH) AF: 0.000325 AC: 6 AN: 18466

⚠️ 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: 0.0000163 AC: 2 AN: 122416 Hom.: 0 Cov.: 28 AF XY: 0.0000169 AC XY: 1 AN XY: 59194

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

American (AMR) AF: 0.0000817 AC: 1 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: 7762

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57840

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

Alfa AF: 0.00 Hom.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=294/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs376068871; hg19: chr17-4851858;