17-4948472-G-A

Position:

• chr17-4948472-G-A

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.-78C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00302 in 1,450,210 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (31 hom.)
• Consequence: PFN1 ENST00000225655.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.74

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=0.0027508438).
• BP6: Variant 17-4948472-G-A is Benign according to our data. Variant chr17-4948472-G-A is described in ClinVar as [Benign]. Clinvar id is 1234360.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 = 0.0152 (2313/152230) while in subpopulation AFR AF= 0.0509 (2116/41536). AF 95% confidence interval is 0.0491. There are 46 homozygotes in gnomad4. There are 1093 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2313 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFN1	NM_005022.4	c.-78C>T		5_prime_UTR_variant	1/3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.-78C>T		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.-78C>T		5_prime_UTR_variant	1/3	1	NM_005022.4	ENSP00000225655	P1
PFN1	ENST00000572383.1	c.160C>T	p.Pro54Ser	missense_variant	2/3	3		ENSP00000460363
ENO3	ENST00000519266.5	c.-3+125G>A		intron_variant		3		ENSP00000467270
ENO3	ENST00000520221.5	c.-3+99G>A		intron_variant		5		ENSP00000467444

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2312 AN: 152118 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00479 AC: 381 AN: 79522 Hom.: 9 AF XY: 0.00344 AC XY: 154 AN XY: 44766

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.000618

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00159 AC: 2069 AN: 1297980 Hom.: 31 Cov.: 27 AF XY: 0.00135 AC XY: 861 AN XY: 635786

Gnomad4 AFR exome AF: 0.0517

Gnomad4 AMR exome AF: 0.00588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000312

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.0152 AC: 2313 AN: 152230 Hom.: 46 Cov.: 33 AF XY: 0.0147 AC XY: 1093 AN XY: 74438

Gnomad4 AFR AF: 0.0509

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.000744 Hom.: 0

Bravo AF: 0.0173

ExAC AF: 0.00410 AC: 458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0028	T
MutationTaster	Benign	1.0	D
MVP		0.74
GERP RS		3.1
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: rs569094456; hg19: chr17-4851767;