rs143766228

Variant names:

• chr5-32400001-A-G
• rs143766228
• NM_016107.5:c.1713+6T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016107.5(ZFR):​c.1713+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,594,980 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (16 hom.)
• Consequence: ZFR NM_016107.5 splice_region, intron
• Scores: Splicing: ADA: 0.06319
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.29
• Publications: 0 publications found

Genes affected

ZFR (HGNC:17277): (zinc finger RNA binding protein) This gene encodes an RNA-binding protein characterized by its DZF (domain associated with zinc fingers) domain. The encoded protein may play a role in the nucleocytoplasmic shuttling of another RNA-binding protein, Staufen homolog 2, in neurons. Expression of this gene is regulated through alternative polyadenylation that mediates differential microRNA targeting. Elevated expression of this gene has been observed in human patients with pancreatic cancer and knockdown of this gene may result in reduced viability and invasion of pancreatic cancer cells. [provided by RefSeq, Sep 2016]

ZFR Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 71

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 5-32400001-A-G is Benign according to our data. Variant chr5-32400001-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 544265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016107.5. 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
	ZFR	NM_016107.5	MANE Select	c.1713+6T>C		splice_region intron	N/A	NP_057191.2
	ZFR	NR_144318.2		n.1795+6T>C		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFR	ENST00000265069.13	TSL:1 MANE Select	c.1713+6T>C		splice_region intron	N/A	ENSP00000265069.8	Q96KR1
	ZFR	ENST00000956812.1		c.1713+6T>C		splice_region intron	N/A	ENSP00000626871.1
	ZFR	ENST00000890167.1		c.1737+6T>C		splice_region intron	N/A	ENSP00000560226.1

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 498 AN: 152188 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00334 AC: 801 AN: 239894 AF XY: 0.00329

Gnomad AFR exome AF: 0.000317

Gnomad AMR exome AF: 0.000850

Gnomad ASJ exome AF: 0.00758

Gnomad EAS exome AF: 0.000283

Gnomad FIN exome AF: 0.00865

Gnomad NFE exome AF: 0.00401

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00360 AC: 5197 AN: 1442674 Hom.: 16 Cov.: 29 AF XY: 0.00356 AC XY: 2550 AN XY: 716936

African (AFR) AF: 0.000487 AC: 16 AN: 32856

American (AMR) AF: 0.000996 AC: 42 AN: 42186

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 199 AN: 25564

East Asian (EAS) AF: 0.000435 AC: 17 AN: 39058

South Asian (SAS) AF: 0.00191 AC: 159 AN: 83126

European-Finnish (FIN) AF: 0.00796 AC: 416 AN: 52250

Middle Eastern (MID) AF: 0.00405 AC: 23 AN: 5682

European-Non Finnish (NFE) AF: 0.00371 AC: 4094 AN: 1102426

Other (OTH) AF: 0.00388 AC: 231 AN: 59526

GnomAD4 genome AF: 0.00327 AC: 498 AN: 152306 Hom.: 2 Cov.: 33 AF XY: 0.00337 AC XY: 251 AN XY: 74476

African (AFR) AF: 0.000722 AC: 30 AN: 41562

American (AMR) AF: 0.00177 AC: 27 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00467 AC: 318 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00429 Hom.: 2

Bravo AF: 0.00254

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Pure or complex autosomal recessive spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.063
dbscSNV1_RF	Benign	0.19
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: rs143766228; hg19: chr5-32400106;