Genetic Variant PFN1:c.-78C>A (chr17-4948472-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005022.4(PFN1):c.-78C>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000077 in 1,297,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

PFN1
NM_005022.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.74

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23201242).

BS2

High AC in GnomAdExome4 at 10 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.-78C>A		5_prime_UTR	Exon 1 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-78C>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.-78C>A		5_prime_UTR	Exon 1 of 3	ENSP00000225655.5	P07737
PFN1	ENST00000572383.1	TSL:3	c.160C>A	p.Pro54Thr	missense	Exon 2 of 3	ENSP00000460363.1	I3L3D5
PFN1	ENST00000929513.1		c.-78C>A		5_prime_UTR	Exon 1 of 3	ENSP00000599572.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

79522

AF XY:

0.00

show subpopulations

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:

0.0000242

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000770

AC:

AN:

1297984

Hom.:

Cov.:

AF XY:

0.00000472

AC XY:

AN XY:

635788

show subpopulations

African (AFR)

AF:

0.0000376

AC:

AN:

26602

American (AMR)

AF:

0.00

AC:

AN:

22808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19566

East Asian (EAS)

AF:

0.0000316

AC:

AN:

31626

South Asian (SAS)

AF:

0.00

AC:

AN:

67288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

0.00000771

AC:

AN:

1037672

Other (OTH)

AF:

0.00

AC:

AN:

53752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0078

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.42

MetaRNN

Benign

0.23

PhyloP100

3.7

MVP

0.74

GERP RS

3.1

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over