17-4945972-T-A

Variant names:

• chr17-4945972-T-A
• rs151313170
• NM_005022.4:c.351A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM1 BP4_Moderate BP6_Very_Strong BS2

The NM_005022.4(PFN1):​c.351A>T​(p.Glu117Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PFN1 NM_005022.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.914
• Publications: 5 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_005022.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.08447835).
• BP6: Variant 17-4945972-T-A is Benign according to our data. Variant chr17-4945972-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1806047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 85 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.351A>T	p.Glu117Asp	missense	Exon 3 of 3	NP_005013.1	P07737
	PFN1	NM_001375991.1		c.*435A>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.351A>T	p.Glu117Asp	missense	Exon 3 of 3	ENSP00000225655.5	P07737
	PFN1	ENST00000896490.1		c.351A>T	p.Glu117Asp	missense	Exon 4 of 4	ENSP00000566549.1
	PFN1	ENST00000896491.1		c.351A>T	p.Glu117Asp	missense	Exon 4 of 4	ENSP00000566550.1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000481 AC: 121 AN: 251480 AF XY: 0.000530

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000993

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00114 AC: 1665 AN: 1460982 Hom.: 1 Cov.: 29 AF XY: 0.00107 AC XY: 781 AN XY: 726858

African (AFR) AF: 0.000120 AC: 4 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00144 AC: 1599 AN: 1111174

Other (OTH) AF: 0.000812 AC: 49 AN: 60378

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74406

African (AFR) AF: 0.000217 AC: 9 AN: 41532

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.069
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.084	T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.91
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.029	D
Polyphen		0.056	B
Vest4		0.28
MutPred		0.67		Loss of ubiquitination at K116 (P = 0.1351)
MVP		0.90
MPC		2.5
ClinPred		0.058	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.93
Mutation Taster		=68/32	polymorphism

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: rs151313170; hg19: chr17-4849267;