rs77829878

Variant names:

• chr5-32395185-T-C
• rs77829878
• NM_016107.5:c.1953A>G
• ZFR p.Glu651Glu

Variant summary

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

The NM_016107.5(ZFR):​c.1953A>G​(p.Glu651Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,605,684 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (85 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (87 hom.)
• Consequence: ZFR NM_016107.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.221
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-32395185-T-C is Benign according to our data. Variant chr5-32395185-T-C is described in ClinVar as Benign. ClinVar VariationId is 544264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.221 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

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.1953A>G	p.Glu651Glu	synonymous	Exon 11 of 20	NP_057191.2
	ZFR	NR_144318.2		n.2035A>G		non_coding_transcript_exon	Exon 11 of 19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFR	ENST00000265069.13	TSL:1 MANE Select	c.1953A>G	p.Glu651Glu	synonymous	Exon 11 of 20	ENSP00000265069.8	Q96KR1
	ZFR	ENST00000956812.1		c.1953A>G	p.Glu651Glu	synonymous	Exon 11 of 21	ENSP00000626871.1
	ZFR	ENST00000890167.1		c.1977A>G	p.Glu659Glu	synonymous	Exon 12 of 21	ENSP00000560226.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2844 AN: 152192 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00475 AC: 1169 AN: 246204 AF XY: 0.00365

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00182 AC: 2638 AN: 1453374 Hom.: 87 Cov.: 31 AF XY: 0.00158 AC XY: 1140 AN XY: 723190

African (AFR) AF: 0.0669 AC: 2208 AN: 33016

American (AMR) AF: 0.00259 AC: 112 AN: 43220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39256

South Asian (SAS) AF: 0.000318 AC: 27 AN: 84972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52982

Middle Eastern (MID) AF: 0.00245 AC: 14 AN: 5720

European-Non Finnish (NFE) AF: 0.0000271 AC: 30 AN: 1108394

Other (OTH) AF: 0.00413 AC: 247 AN: 59858

GnomAD4 genome AF: 0.0188 AC: 2857 AN: 152310 Hom.: 85 Cov.: 32 AF XY: 0.0184 AC XY: 1373 AN XY: 74468

African (AFR) AF: 0.0660 AC: 2741 AN: 41560

American (AMR) AF: 0.00536 AC: 82 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00995 Hom.: 22

Bravo AF: 0.0210

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.6
DANN	Benign	0.53
PhyloP100		-0.22
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8
Mutation Taster		=90/10	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77829878;

hg19: chr5-32395291;

COSMIC: COSV104370012;