chr8-31033929-C-G

Variant names:

• chr8-31033929-C-G
• rs1563314112
• NM_000553.6:c.-121C>G

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_000553.6(WRN):c.-121C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The gene WRN is a tumor suppressor gene (CancerMine: 3 TSG citations). The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,202 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: WRN NM_000553.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.413
• Publications: 0 publications found

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN Gene-Disease associations (from GenCC):

• Werner syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

PURG (HGNC:17930): (purine rich element binding protein G) The exact function of this gene is not known, however, its encoded product is highly similar to purine-rich element binding protein A. The latter is a DNA-binding protein which binds preferentially to the single strand of the purine-rich element termed PUR, and has been implicated in the control of both DNA replication and transcription. This gene lies in close proximity to the Werner syndrome gene, but on the opposite strand, on chromosome 8p11. [provided by RefSeq, Apr 2016]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000015, AC = 1 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000553.6. 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
	WRN NM_000553.6	MANE Select	c.-121C>G	5_prime_UTR	Exon 1 of 35	Prot: NP_000544.2 UniProt:

WRN NM_000553.6

MANE Select

HGVSc / HGVSpc.-121C>G

Exon rankExon 1 of 35

5_prime_UTR

Prot: NP_000544.2UniProt: Q14191

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	WRN ENST00000298139.7	TSL:1MANE Select	c.-121C>G	5_prime_UTR	Exon 1 of 35	Prot: ENSP00000298139.5 UniProt:
	WRN ENST00000966176.1		c.-121C>G	5_prime_UTR	Exon 1 of 35	Prot: ENSP00000636235.1 UniProt:
	WRN ENST00000860283.1		c.-110C>G	5_prime_UTR	Exon 1 of 35	Prot: ENSP00000530342.1 UniProt:

WRN ENST00000298139.7

TSL:1MANE Select

HGVSc / HGVSpc.-121C>G

Exon rankExon 1 of 35

5_prime_UTR

Prot: ENSP00000298139.5UniProt: Q14191

WRN ENST00000966176.1

HGVSc / HGVSpc.-121C>G

Exon rankExon 1 of 35

5_prime_UTR

Prot: ENSP00000636235.1UniProt: A0ACI8VD15

WRN ENST00000860283.1

HGVSc / HGVSpc.-110C>G

Exon rankExon 1 of 35

5_prime_UTR

Prot: ENSP00000530342.1UniProt: Q14191

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152202	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:0
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152202	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Werner syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.8
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.70
GPN-Star LLR	N/A	-0.94
GPN-Star score	N/A	0.94
PhyloP100	Benign	0.41
PromoterAI	N/A	-0.021	Neutral
RBP_binding_hub_radar	N/A	0.92
RBP_regulation_power_radar	N/A	2.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1563314112;

hg19: chr8-30891445;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar