NM_005022.4:c.334C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005022.4(PFN1):c.334C>T(p.Leu112Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0471 in 1,610,122 control chromosomes in the GnomAD database, including 3,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 317 hom., cov: 32)

Exomes 𝑓: 0.047 ( 2789 hom. )

Consequence

PFN1
NM_005022.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0170

Publications

18 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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 18
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PFN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 17-4945989-G-A is Benign according to our data. Variant chr17-4945989-G-A is described in ClinVar as Benign. ClinVar VariationId is 259607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.017 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4 link	c.334C>T	p.Leu112Leu	synonymous_variant	Exon 3 of 3	ENST00000225655.6	NP_005013.1	P07737
PFN1	NM_001375991.1 link	c.*418C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6 link	c.334C>T	p.Leu112Leu	synonymous_variant	Exon 3 of 3	1	NM_005022.4	ENSP00000225655.5		P07737
PFN1	ENST00000574872.1 link	c.226C>T	p.Leu76Leu	synonymous_variant	Exon 2 of 2	2		ENSP00000465019.1		K7EJ44

Frequencies

GnomAD3 genomes

AF:

0.0502

AC:

7630

AN:

152006

Hom.:

317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.0994

Gnomad FIN

AF:

0.0245

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0366

Gnomad OTH

AF:

0.0556

GnomAD2 exomes

AF:

0.0700

AC:

17602

AN:

251406

AF XY:

0.0680

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.0631

Gnomad EAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.0258

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

AF:

0.0468

AC:

68194

AN:

1457998

Hom.:

2789

Cov.:

AF XY:

0.0482

AC XY:

35005

AN XY:

725604

show subpopulations

African (AFR)

AF:

0.0255

AC:

852

AN:

33392

American (AMR)

AF:

0.137

AC:

6137

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0622

AC:

1623

AN:

26110

East Asian (EAS)

AF:

0.220

AC:

8727

AN:

39666

South Asian (SAS)

AF:

0.0958

AC:

8250

AN:

86118

European-Finnish (FIN)

AF:

0.0268

AC:

1430

AN:

53406

Middle Eastern (MID)

AF:

0.0757

AC:

436

AN:

5760

European-Non Finnish (NFE)

AF:

0.0337

AC:

37331

AN:

1108586

Other (OTH)

AF:

0.0566

AC:

3408

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

2748

5497

8245

10994

13742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1574

3148

4722

6296

7870

<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:

0.0502

AC:

7631

AN:

152124

Hom.:

317

Cov.:

AF XY:

0.0531

AC XY:

3949

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0275

AC:

1141

AN:

41514

American (AMR)

AF:

0.123

AC:

1875

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0536

AC:

186

AN:

3468

East Asian (EAS)

AF:

0.202

AC:

1039

AN:

5154

South Asian (SAS)

AF:

0.0985

AC:

474

AN:

4814

European-Finnish (FIN)

AF:

0.0245

AC:

260

AN:

10600

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0366

AC:

2487

AN:

67984

Other (OTH)

AF:

0.0540

AC:

114

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

342

683

1025

1366

1708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0402

Hom.:

Bravo

AF:

0.0569

Asia WGS

AF:

0.126

AC:

437

AN:

3478

EpiCase

AF:

0.0394

EpiControl

AF:

0.0389

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 18

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

-0.017

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over