17-4948452-G-C

Variant names:

• chr17-4948452-G-C
• rs140177490
• NM_005022.4:c.-58C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 818 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.-58C>G		5_prime_UTR	Exon 1 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-58C>G		5_prime_UTR	Exon 1 of 2	NP_001362920.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFN1	ENST00000225655.6	TSL:1 MANE Select	c.-58C>G		5_prime_UTR	Exon 1 of 3	ENSP00000225655.5	P07737
	PFN1	ENST00000572383.1	TSL:3	c.180C>G	p.Ser60Arg	missense	Exon 2 of 3	ENSP00000460363.1	I3L3D5
	PFN1	ENST00000896490.1		c.-58C>G		5_prime_UTR	Exon 2 of 4	ENSP00000566549.1

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

GnomAD2 exomes AF: 0.00138 AC: 188 AN: 136716 AF XY: 0.000887

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 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

African (AFR) AF: 0.0180 AC: 504 AN: 27954

American (AMR) AF: 0.00186 AC: 56 AN: 30136

Ashkenazi Jewish (ASJ) AF: 0.0000459 AC: 1 AN: 21800

East Asian (EAS) AF: 0.00 AC: 0 AN: 33450

South Asian (SAS) AF: 0.0000672 AC: 5 AN: 74372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37454

Middle Eastern (MID) AF: 0.000928 AC: 5 AN: 5388

European-Non Finnish (NFE) AF: 0.0000667 AC: 71 AN: 1065026

Other (OTH) AF: 0.00161 AC: 90 AN: 55796

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

African (AFR) AF: 0.0182 AC: 757 AN: 41576

American (AMR) AF: 0.00340 AC: 52 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.00609

ExAC AF: 0.00139 AC: 163

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
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
PhyloP100		1.9
MVP		0.78
GERP RS		1.2
PromoterAI		-0.021	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs140177490; hg19: chr17-4851747;