17-4948526-G-C

Variant names:

• chr17-4948526-G-C
• rs760016635
• NM_005022.4:c.-132C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005022.4(PFN1):​c.-132C>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 0.00000343 in 874,658 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: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PFN1 NM_005022.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17946842).

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.-132C>G		5_prime_UTR	Exon 1 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.-132C>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.-132C>G		5_prime_UTR	Exon 1 of 3	ENSP00000225655.5	P07737
	PFN1	ENST00000572383.1	TSL:3	c.106C>G	p.Arg36Gly	missense	Exon 2 of 3	ENSP00000460363.1	I3L3D5
	PFN1	ENST00000929513.1		c.-132C>G		5_prime_UTR	Exon 1 of 3	ENSP00000599572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 3 AN: 874658 Hom.: 0 Cov.: 11 AF XY: 0.00000461 AC XY: 2 AN XY: 433720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16944

American (AMR) AF: 0.00 AC: 0 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14610

East Asian (EAS) AF: 0.0000761 AC: 2 AN: 26268

South Asian (SAS) AF: 0.00 AC: 0 AN: 48274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3430

European-Non Finnish (NFE) AF: 0.00000146 AC: 1 AN: 686642

Other (OTH) AF: 0.00 AC: 0 AN: 38720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0245704), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.73
DEOGEN2	Benign	0.0062	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.18	T
PhyloP100		2.0
MVP		0.61
GERP RS		1.6
PromoterAI		-0.037	Neutral

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

Other links and lift over

dbSNP: rs760016635; hg19: chr17-4851821;