chr17-4948563-T-TC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000572383.1(PFN1):​c.77-9_77-8insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 458,360 control chromosomes in the GnomAD database, including 383 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.064 (323 hom., cov: 28)
  • Exomes 𝑓: 0.076 (60 hom.)
• Consequence: PFN1 ENST00000572383.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-4948563-T-TC is Benign according to our data. Variant chr17-4948563-T-TC is described in ClinVar as Benign. ClinVar VariationId is 1295407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 7783 AN: 122194 Hom.: 324 Cov.: 28

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0386

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0630

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0709

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.0733

GnomAD2 exomes AF: 0.0633 AC: 59 AN: 932 AF XY: 0.0611

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.0625

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0756 AC: 25398 AN: 336136 Hom.: 60 Cov.: 3 AF XY: 0.0781 AC XY: 13508 AN XY: 172990

African (AFR) AF: 0.0460 AC: 311 AN: 6764

American (AMR) AF: 0.152 AC: 954 AN: 6256

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 742 AN: 8780

East Asian (EAS) AF: 0.237 AC: 4522 AN: 19082

South Asian (SAS) AF: 0.126 AC: 2731 AN: 21640

European-Finnish (FIN) AF: 0.0585 AC: 1265 AN: 21620

Middle Eastern (MID) AF: 0.0879 AC: 124 AN: 1410

European-Non Finnish (NFE) AF: 0.0568 AC: 13206 AN: 232378

Other (OTH) AF: 0.0848 AC: 1543 AN: 18206

GnomAD4 genome AF: 0.0636 AC: 7776 AN: 122224 Hom.: 323 Cov.: 28 AF XY: 0.0649 AC XY: 3837 AN XY: 59096

African (AFR) AF: 0.0362 AC: 1125 AN: 31100

American (AMR) AF: 0.133 AC: 1619 AN: 12180

Ashkenazi Jewish (ASJ) AF: 0.0630 AC: 187 AN: 2968

East Asian (EAS) AF: 0.193 AC: 803 AN: 4156

South Asian (SAS) AF: 0.117 AC: 427 AN: 3658

European-Finnish (FIN) AF: 0.0408 AC: 316 AN: 7742

Middle Eastern (MID) AF: 0.0783 AC: 18 AN: 230

European-Non Finnish (NFE) AF: 0.0542 AC: 3133 AN: 57766

Other (OTH) AF: 0.0722 AC: 117 AN: 1620

Alfa AF: 0.0141 Hom.: 36

ClinVar

ClinVar submissions as Germline

Significance: Benign

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		3.3
Mutation Taster		=298/2	polymorphism (auto)

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; COSMIC: COSV52591542; COSMIC: COSV52591542;