NM_005022.4:c.334C>T

Variant names:

• chr17-4945989-G-A
• rs13204
• NM_005022.4:c.334C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005022.4(PFN1):​c.334C>T​(p.Leu112Leu) 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:8
• Conservation: PhyloP100: -0.0170
• Publications: 18 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]

PFN1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.334C>T	p.Leu112Leu	synonymous	Exon 3 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.*418C>T		3_prime_UTR	Exon 2 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.334C>T	p.Leu112Leu	synonymous	Exon 3 of 3	ENSP00000225655.5	P07737
	PFN1	ENST00000896490.1		c.334C>T	p.Leu112Leu	synonymous	Exon 4 of 4	ENSP00000566549.1
	PFN1	ENST00000896491.1		c.334C>T	p.Leu112Leu	synonymous	Exon 4 of 4	ENSP00000566550.1

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

GnomAD2 exomes AF: 0.0700 AC: 17602 AN: 251406 AF XY: 0.0680

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 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

African (AFR) AF: 0.0255 AC: 852 AN: 33392

American (AMR) AF: 0.137 AC: 6137 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 1623 AN: 26110

East Asian (EAS) AF: 0.220 AC: 8727 AN: 39666

South Asian (SAS) AF: 0.0958 AC: 8250 AN: 86118

European-Finnish (FIN) AF: 0.0268 AC: 1430 AN: 53406

Middle Eastern (MID) AF: 0.0757 AC: 436 AN: 5760

European-Non Finnish (NFE) AF: 0.0337 AC: 37331 AN: 1108586

Other (OTH) AF: 0.0566 AC: 3408 AN: 60252

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

African (AFR) AF: 0.0275 AC: 1141 AN: 41514

American (AMR) AF: 0.123 AC: 1875 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3468

East Asian (EAS) AF: 0.202 AC: 1039 AN: 5154

South Asian (SAS) AF: 0.0985 AC: 474 AN: 4814

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10600

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0366 AC: 2487 AN: 67984

Other (OTH) AF: 0.0540 AC: 114 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Amyotrophic lateral sclerosis type 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		-0.017
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

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