5-32403235-T-G

Variant names:

• chr5-32403235-T-G
• rs150408674
• NM_016107.5:c.1387A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016107.5(ZFR):​c.1387A>C​(p.Thr463Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T463M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFR NM_016107.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07695684).

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.1387A>C	p.Thr463Pro	missense	Exon 8 of 20	NP_057191.2
	ZFR	NR_144318.2		n.1469A>C		non_coding_transcript_exon	Exon 8 of 19

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFR	ENST00000265069.13	TSL:1 MANE Select	c.1387A>C	p.Thr463Pro	missense	Exon 8 of 20	ENSP00000265069.8	Q96KR1
	ZFR	ENST00000956812.1		c.1387A>C	p.Thr463Pro	missense	Exon 8 of 21	ENSP00000626871.1
	ZFR	ENST00000890167.1		c.1411A>C	p.Thr471Pro	missense	Exon 9 of 21	ENSP00000560226.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.078
Sift	Benign	0.12	T
Sift4G	Benign	0.35	T
Polyphen		0.079	B
Vest4		0.16
MutPred		0.15		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.082
MPC		0.059
ClinPred		0.19	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.23
Mutation Taster		=85/15	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: rs150408674; hg19: chr5-32403340;