chr2-135218928-A-T

Variant names:

• chr2-135218928-A-T
• rs4954228
• NM_032143.4:c.2352+149T>A

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_032143.4(ZRANB3):c.2352+149T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene ZRANB3 is a tumor suppressor gene (CancerMine: 1 TSG citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: not found (cov: 32)
• Consequence: ZRANB3 NM_032143.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 publications found

Genes affected

ZRANB3 (HGNC:25249): (zinc finger RANBP2-type containing 3) Enables ATP-dependent DNA/DNA annealing activity; DNA endonuclease activity; and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in DNA repair; replication fork reversal; and response to UV. Located in nuclear replication fork and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

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 = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_032143.4. 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
	ZRANB3 NM_032143.4	MANE Select	c.2352+149T>A	intron	Intron 16 of 20	Prot: NP_115519.2 UniProt:
	ZRANB3 NM_001286568.2		c.2346+149T>A	intron	Intron 16 of 20	Prot: NP_001273497.1 UniProt:
	ZRANB3 NM_001286569.1		c.990+149T>A	intron	Intron 17 of 21	Prot: NP_001273498.1 UniProt:

ZRANB3 NM_032143.4

MANE Select

HGVSc / HGVSpc.2352+149T>A

Exon rankIntron 16 of 20

intron

Prot: NP_115519.2UniProt: Q5FWF4-1

ZRANB3 NM_001286568.2

HGVSc / HGVSpc.2346+149T>A

Exon rankIntron 16 of 20

intron

Prot: NP_001273497.1UniProt: Q5FWF4-3

ZRANB3 NM_001286569.1

HGVSc / HGVSpc.990+149T>A

Exon rankIntron 17 of 21

intron

Prot: NP_001273498.1UniProt: F5GYN7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZRANB3 ENST00000264159.11	TSL:1MANE Select	c.2352+149T>A	intron	Intron 16 of 20	Prot: ENSP00000264159.6 UniProt:
	ZRANB3 ENST00000401392.5	TSL:1	c.2346+149T>A	intron	Intron 16 of 20	Prot: ENSP00000383979.1 UniProt:
	ZRANB3 ENST00000536680.5	TSL:1	c.990+149T>A	intron	Intron 17 of 21	Prot: ENSP00000441320.2 UniProt:

ZRANB3 ENST00000264159.11

TSL:1MANE Select

HGVSc / HGVSpc.2352+149T>A

Exon rankIntron 16 of 20

intron

Prot: ENSP00000264159.6UniProt: Q5FWF4-1

ZRANB3 ENST00000401392.5

TSL:1

HGVSc / HGVSpc.2346+149T>A

Exon rankIntron 16 of 20

intron

Prot: ENSP00000383979.1UniProt: Q5FWF4-3

ZRANB3 ENST00000536680.5

TSL:1

HGVSc / HGVSpc.990+149T>A

Exon rankIntron 17 of 21

intron

Prot: ENSP00000441320.2UniProt: F5GYN7

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122800	Cov:

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.9
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.0
DANN	Benign	0.37
GPN-Star LLR	N/A	-1.1
GPN-Star score	N/A	1.1
PhyloP100	Benign	1.1

Showing 7 of 7 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.

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: rs4954228;

hg19: chr2-135976498;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar