Genetic Variant ZPR1:p.Phe387Leu (chr11-116782176-A-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003904.5(ZPR1):c.1161T>A(p.Phe387Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,614,064 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 56 hom. )

Consequence

ZPR1
NM_003904.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.344

Publications

11 publications found

Variant links:

Genes affected

ZPR1 (HGNC:13051): (ZPR1 zinc finger) The protein encoded by this gene is found in the cytoplasm of quiescent cells but translocates to the nucleolus in proliferating cells. The encoded protein interacts with survival motor neuron protein (SMN1) to enhance pre-mRNA splicing and to induce neuronal differentiation and axonal growth. Defects in this gene or the SMN1 gene can cause spinal muscular atrophy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

ZPR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011996299).

BP6

Variant 11-116782176-A-T is Benign according to our data. Variant chr11-116782176-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2642396.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003904.5. 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
	ZPR1	NM_003904.5	MANE Select	c.1161T>A	p.Phe387Leu	missense	Exon 12 of 14	NP_003895.1	O75312
	ZPR1	NM_001317086.2		c.999T>A	p.Phe333Leu	missense	Exon 11 of 13	NP_001304015.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZPR1	ENST00000227322.8	TSL:1 MANE Select	c.1161T>A	p.Phe387Leu	missense	Exon 12 of 14	ENSP00000227322.3	O75312
ZPR1	ENST00000900046.1		c.1191T>A	p.Phe397Leu	missense	Exon 12 of 14	ENSP00000570105.1
ZPR1	ENST00000900049.1		c.1167T>A	p.Phe389Leu	missense	Exon 12 of 14	ENSP00000570108.1

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

791

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00772

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00495

AC:

1243

AN:

251340

AF XY:

0.00470

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00823

Gnomad NFE exome

AF:

0.00785

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00674

AC:

9857

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

4695

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33474

American (AMR)

AF:

0.00322

AC:

144

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00809

AC:

432

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00797

AC:

8858

AN:

1111914

Other (OTH)

AF:

0.00576

AC:

348

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

448

896

1345

1793

2241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

322

644

966

1288

1610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00519

AC:

791

AN:

152312

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

377

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41562

American (AMR)

AF:

0.00425

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00998

AC:

106

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00772

AC:

525

AN:

68022

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00697

Hom.:

Bravo

AF:

0.00500

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00803

AC:

ExAC

AF:

0.00488

AC:

592

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00715

EpiControl

AF:

0.00557

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Benign

0.016

Eigen_PC

Benign

0.0023

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

M_CAP

Benign

0.046

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.6

PhyloP100

0.34

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.28

Sift

Benign

0.042

Sift4G

Uncertain

0.055

Polyphen

0.97

Vest4

0.73

MutPred

0.78

Gain of disorder (P = 0.1458)

MVP

0.48

MPC

1.1

ClinPred

0.057

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.73

Mutation Taster

=76/24

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over