rs13204

chr17-4945989-G-Achr17-4945989-G-Cchr17-4945989-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005022.4(PFN1):c.334C>T(p.Leu112=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0471 in 1,610,122 control chromosomes in the GnomAD database, including 3,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (317 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2789 hom.)
• Consequence: PFN1 NM_005022.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0170

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 17-4945989-G-A is Benign according to our data. Variant chr17-4945989-G-A is described in ClinVar as [Benign]. Clinvar id is 259607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4945989-G-A is described in Lovd as [Benign]. Variant chr17-4945989-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.017 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFN1	NM_005022.4	c.334C>T	p.Leu112=	synonymous_variant	3/3	ENST00000225655.6
PFN1	NM_001375991.1	c.*418C>T		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFN1	ENST00000225655.6	c.334C>T	p.Leu112=	synonymous_variant	3/3	1	NM_005022.4	P1
PFN1	ENST00000574872.1	c.226C>T	p.Leu76=	synonymous_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7630 AN: 152006 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.0994

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0366

Gnomad OTH AF: 0.0556

GnomAD3 exomes AF: 0.0700 AC: 17602 AN: 251406 Hom.: 968 AF XY: 0.0680 AC XY: 9237 AN XY: 135890

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0631

Gnomad EAS exome AF: 0.200

Gnomad SAS exome AF: 0.0941

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.0366

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0468 AC: 68194 AN: 1457998 Hom.: 2789 Cov.: 29 AF XY: 0.0482 AC XY: 35005 AN XY: 725604

Gnomad4 AFR exome AF: 0.0255

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.0622

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.0958

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0337

Gnomad4 OTH exome AF: 0.0566

GnomAD4 genome AF: 0.0502 AC: 7631 AN: 152124 Hom.: 317 Cov.: 32 AF XY: 0.0531 AC XY: 3949 AN XY: 74376

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0536

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.0985

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0366

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0402 Hom.: 73

Bravo AF: 0.0569

Asia WGS AF: 0.126 AC: 437 AN: 3478

EpiCase AF: 0.0394

EpiControl AF: 0.0389

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Amyotrophic lateral sclerosis type 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	12
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13204; hg19: chr17-4849284; COSMIC: COSV52591045; COSMIC: COSV52591045;