chr17-4948472-G-A

Variant names:

• chr17-4948472-G-A
• rs569094456
• NM_005022.4:c.-78C>T

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.-78C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00302 in 1,450,210 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (31 hom.)
• Consequence: PFN1 NM_005022.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.74

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027508438).
• BP6: Variant 17-4948472-G-A is Benign according to our data. Variant chr17-4948472-G-A is described in ClinVar as [Benign]. Clinvar id is 1234360.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 = 0.0152 (2313/152230) while in subpopulation AFR AF = 0.0509 (2116/41536). AF 95% confidence interval is 0.0491. There are 46 homozygotes in GnomAd4. There are 1093 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 2313 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFN1	NM_005022.4	c.-78C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000225655.6	NP_005013.1
PFN1	NM_001375991.1	c.-78C>T		5_prime_UTR_variant	Exon 1 of 2		NP_001362920.1
ENO3	XM_011523729.2	c.-824G>A		upstream_gene_variant			XP_011522031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFN1	ENST00000225655.6	c.-78C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_005022.4	ENSP00000225655.5
PFN1	ENST00000572383.1	c.160C>T	p.Pro54Ser	missense_variant	Exon 2 of 3	3		ENSP00000460363.1
ENO3	ENST00000520221.5	c.-3+99G>A		intron_variant	Intron 1 of 6	5		ENSP00000467444.1
ENO3	ENST00000519266.5	c.-3+125G>A		intron_variant	Intron 1 of 1	3		ENSP00000467270.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2312 AN: 152118 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00479 AC: 381 AN: 79522 AF XY: 0.00344

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00159 AC: 2069 AN: 1297980 Hom.: 31 Cov.: 27 AF XY: 0.00135 AC XY: 861 AN XY: 635786

Gnomad4 AFR exome AF: 0.0517 AC: 1374 AN: 26600

Gnomad4 AMR exome AF: 0.00588 AC: 134 AN: 22808

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19566

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 31626

Gnomad4 SAS exome AF: 0.000312 AC: 21 AN: 67288

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 33460

Gnomad4 NFE exome AF: 0.000312 AC: 324 AN: 1037670

Gnomad4 Remaining exome AF: 0.00378 AC: 203 AN: 53752

GnomAD4 genome AF: 0.0152 AC: 2313 AN: 152230 Hom.: 46 Cov.: 33 AF XY: 0.0147 AC XY: 1093 AN XY: 74438

Gnomad4 AFR AF: 0.0509 AC: 0.0509438 AN: 0.0509438

Gnomad4 AMR AF: 0.00824 AC: 0.00823529 AN: 0.00823529

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000193274 AN: 0.000193274

Gnomad4 SAS AF: 0.000622 AC: 0.000621633 AN: 0.000621633

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000529 AC: 0.000529458 AN: 0.000529458

Gnomad4 OTH AF: 0.0147 AC: 0.014678 AN: 0.014678

Alfa AF: 0.000744 Hom.: 0

Bravo AF: 0.0173

ExAC AF: 0.00410 AC: 458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0028	T
MVP		0.74
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=294/6	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

Publications

LitVar

Other links and lift over

dbSNP: rs569094456; hg19: chr17-4851767;