17-4948480-C-T

Position:

• chr17-4948480-C-T

Variant summary

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

The ENST00000225655.6(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 ENST00000225655.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10

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=0.00483343).
• 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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2099 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4	c.-86G>A		5_prime_UTR_variant	1/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.-86G>A		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.-86G>A		5_prime_UTR_variant	1/3	1	NM_005022.4	ENSP00000225655	P1
PFN1	ENST00000572383.1	c.152G>A	p.Arg51His	missense_variant	2/3	3		ENSP00000460363
ENO3	ENST00000519266.5	c.-3+133C>T		intron_variant		3		ENSP00000467270
ENO3	ENST00000520221.5	c.-3+107C>T		intron_variant		5		ENSP00000467444

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2100 AN: 151908 Hom.: 22 Cov.: 33

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

GnomAD3 exomes AF: 0.0203 AC: 1181 AN: 58052 Hom.: 18 AF XY: 0.0197 AC XY: 638 AN XY: 32414

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 SAS exome AF: 0.00357

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.: 23 AF XY: 0.0214 AC XY: 13148 AN XY: 615766

Gnomad4 AFR exome AF: 0.00304

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0000329

Gnomad4 SAS exome AF: 0.00269

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0138 AC: 2099 AN: 152018 Hom.: 22 Cov.: 33 AF XY: 0.0124 AC XY: 922 AN XY: 74314

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0225

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0207 Hom.: 4

Bravo AF: 0.0137

ExAC AF: 0.0111 AC: 1150

Asia WGS AF: 0.00173 AC: 6 AN: 3476

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0048	T
MutationTaster	Benign	1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

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: rs11538685; hg19: chr17-4851775;