17-4948452-G-C

Position:

• chr17-4948452-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005022.4(PFN1):​c.-58C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,503,660 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: PFN1 NM_005022.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.88

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060488284).
• BP6: Variant 17-4948452-G-C is Benign according to our data. Variant chr17-4948452-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1199737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00537 (818/152284) while in subpopulation AFR AF= 0.0182 (757/41576). AF 95% confidence interval is 0.0171. There are 5 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 818 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4	c.-58C>G		5_prime_UTR_variant	1/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.-58C>G		5_prime_UTR_variant	1/2		NP_001362920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6	c.-58C>G		5_prime_UTR_variant	1/3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000572383.1	c.180C>G	p.Ser60Arg	missense_variant	2/3	3		ENSP00000460363.1
ENO3	ENST00000520221.5	c.-3+79G>C		intron_variant		5		ENSP00000467444.1
ENO3	ENST00000519266.5	c.-3+105G>C		intron_variant		3		ENSP00000467270.1

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 816 AN: 152170 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

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: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00138 AC: 188 AN: 136716 Hom.: 3 AF XY: 0.000887 AC XY: 69 AN XY: 77772

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000431

Gnomad OTH exome AF: 0.000645

GnomAD4 exome AF: 0.000542 AC: 732 AN: 1351376 Hom.: 4 Cov.: 33 AF XY: 0.000497 AC XY: 331 AN XY: 666314

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000672

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000667

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152284 Hom.: 5 Cov.: 33 AF XY: 0.00466 AC XY: 347 AN XY: 74464

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.00609

ExAC AF: 0.00139 AC: 163

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.0057	T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0060	T
MVP		0.78
GERP RS		1.2

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

LitVar

Other links and lift over

dbSNP: rs140177490; hg19: chr17-4851747;