17-4948480-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005022.4(PFN1):c.-86G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,412,236 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 22 hom., cov: 33)

Exomes 𝑓: 0.022 ( 363 hom. )

Consequence

PFN1
NM_005022.4 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.10

Publications

3 publications found

Variant links:

Genes affected

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 links:

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]

ENO3 Gene-Disease associations (from GenCC):

glycogen storage disease due to muscle beta-enolase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ENO3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00483343).

BP6

Variant 17-4948480-C-T is Benign according to our data. Variant chr17-4948480-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1215785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (2099/152018) while in subpopulation NFE AF = 0.0225 (1530/67924). AF 95% confidence interval is 0.0216. There are 22 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2099 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005022.4. 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.-86G>A		5_prime_UTR	Exon 1 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-86G>A		5_prime_UTR	Exon 1 of 2	NP_001362920.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PFN1	ENST00000225655.6	TSL:1 MANE Select	c.-86G>A		5_prime_UTR	Exon 1 of 3	ENSP00000225655.5	P07737
PFN1	ENST00000572383.1	TSL:3	c.152G>A	p.Arg51His	missense	Exon 2 of 3	ENSP00000460363.1	I3L3D5
PFN1	ENST00000929513.1		c.-86G>A		5_prime_UTR	Exon 1 of 3	ENSP00000599572.1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2100

AN:

151908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0225

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0203

AC:

1181

AN:

58052

AF XY:

0.0197

show subpopulations

Gnomad AFR exome

AF:

0.00497

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0235

Gnomad NFE exome

AF:

0.0298

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0220

AC:

27751

AN:

1260218

Hom.:

363

Cov.:

AF XY:

0.0214

AC XY:

13148

AN XY:

615766

show subpopulations

African (AFR)

AF:

0.00304

AC:

AN:

25662

American (AMR)

AF:

0.0118

AC:

231

AN:

19620

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

327

AN:

18722

East Asian (EAS)

AF:

0.0000329

AC:

AN:

30440

South Asian (SAS)

AF:

0.00269

AC:

172

AN:

64044

European-Finnish (FIN)

AF:

0.0139

AC:

444

AN:

31844

Middle Eastern (MID)

AF:

0.00380

AC:

AN:

4994

European-Non Finnish (NFE)

AF:

0.0252

AC:

25499

AN:

1012582

Other (OTH)

AF:

0.0187

AC:

980

AN:

52310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1314

2628

3942

5256

6570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

992

1984

2976

3968

4960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0138

AC:

2099

AN:

152018

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00371

AC:

154

AN:

41488

American (AMR)

AF:

0.0125

AC:

191

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00166

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0110

AC:

117

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0225

AC:

1530

AN:

67924

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

189

283

378

472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0207

Hom.:

Bravo

AF:

0.0137

ExAC

AF:

0.0111

AC:

1150

Asia WGS

AF:

0.00173

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0080

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0048

PhyloP100

1.1

GERP RS

4.2

PromoterAI

-0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over