rs964184

Variant names:

• chr11-116778201-G-C
• rs964184
• NM_003904.5:c.*724C>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_003904.5(ZPR1):c.*724C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.823 (AC=125,282) in the gnomAD database across 152,238 control chromosomes, including 51,799 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.856. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (51773 hom., cov: 32)
  • Exomes 𝑓: 0.88 (26 hom.)
• Consequence: ZPR1 NM_003904.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• Publications: 515 publications found

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 Gene-Disease associations (from GenCC):

• growth restriction, hypoplastic kidneys, alopecia, and distinctive facies

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8562 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003904.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZPR1	NM_003904.5	MANE Select	c.*724C>G		3_prime_UTR	Exon 14 of 14	NP_003895.1	O75312
	ZPR1	NM_001317086.2		c.*724C>G		3_prime_UTR	Exon 13 of 13	NP_001304015.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZPR1	ENST00000227322.8	TSL:1 MANE Select	c.*724C>G		3_prime_UTR	Exon 14 of 14	ENSP00000227322.3	O75312
	ZPR1	ENST00000900046.1		c.*724C>G		3_prime_UTR	Exon 14 of 14	ENSP00000570105.1	A0ACI8SFC3
	ZPR1	ENST00000444935.5	TSL:5	c.*724C>G		3_prime_UTR	Exon 13 of 13	ENSP00000390391.1	H7BZM7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.823	AC:125152	Hom:51754	AN:152052	Cov:32
GnomAD4 exome	AF: 0.882	AC:60	Hom:26	AN:68	Cov:0
GnomAD4 genome	AF: 0.823	AC:125222	Hom:51773	AN:152170	Cov:32
TOPMed (Bravo)	AF: 0.813	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.850	AC:76593	Hom:32598	AN:90100	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.814	AC:1907	Hom:775	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.786	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.837	AC:251	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.765	AC:2662	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.776	AC:5609	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.807	AC:142	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.730	AC:89638	Hom:32789	AN:122814	Cov:
Turkish Variome	AF: 0.809	AC:1251	Hom:508	AN:1546	Cov:
UK10K	AF: 0.867	AC:6555	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.783	AC:7012	Hom:2759	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.348	7902	22684	0.165	4818	29188

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.0
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.48
DANN	Benign	0.42
GPN-Star LLR	N/A	3.7
GPN-Star score	N/A	-0.76
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.35

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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: rs964184;

hg19: chr11-116648917;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar