chr14-103712930-T-A

Variant names:

• chr14-103712930-T-A
• rs1799794
• NM_005432.4:c.-316A>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Strong

The NM_005432.4(XRCC3):c.-316A>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000207, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. 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 0.0000066 (0 hom., cov: 34)
• Consequence: XRCC3 NM_005432.4 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00003480
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.429
• Publications: 14 publications found

Genes affected

XRCC3 (HGNC:12830): (X-ray repair cross complementing 3) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000207 — borderline rare for unknown gene (threshold 0.001) — PM2 supporting.
	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).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005432.4. 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
	XRCC3 NM_005432.4	MANE Select	c.-316A>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	Prot: NP_005423.1 UniProt:
	XRCC3 NM_005432.4	MANE Select	c.-316A>T	splice_region	Exon 2 of 10	Prot: NP_005423.1 UniProt:
	XRCC3 NM_005432.4	MANE Select	c.-316A>T	5_prime_UTR	Exon 2 of 10	Prot: NP_005423.1 UniProt:

XRCC3 NM_005432.4

MANE Select

HGVSc / HGVSpc.-316A>T

Exon rankExon 2 of 10

5_prime_UTR_premature_start_codon_gain

Prot: NP_005423.1UniProt: Q53XC8O43542

XRCC3 NM_005432.4

MANE Select

HGVSc / HGVSpc.-316A>T

Exon rankExon 2 of 10

splice_region

Prot: NP_005423.1UniProt: Q53XC8O43542

XRCC3 NM_005432.4

MANE Select

HGVSc / HGVSpc.-316A>T

Exon rankExon 2 of 10

5_prime_UTR

Prot: NP_005423.1UniProt: Q53XC8O43542

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	XRCC3 ENST00000555055.6	TSL:1MANE Select	c.-316A>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	Prot: ENSP00000452598.1 UniProt:
	XRCC3 ENST00000555055.6	TSL:1MANE Select	c.-316A>T	splice_region	Exon 2 of 10	Prot: ENSP00000452598.1 UniProt:
	XRCC3 ENST00000555055.6	TSL:1MANE Select	c.-316A>T	5_prime_UTR	Exon 2 of 10	Prot: ENSP00000452598.1 UniProt:

XRCC3 ENST00000555055.6

TSL:1MANE Select

HGVSc / HGVSpc.-316A>T

Exon rankExon 2 of 10

5_prime_UTR_premature_start_codon_gain

Prot: ENSP00000452598.1UniProt: O43542

XRCC3 ENST00000555055.6

TSL:1MANE Select

HGVSc / HGVSpc.-316A>T

Exon rankExon 2 of 10

splice_region

Prot: ENSP00000452598.1UniProt: O43542

XRCC3 ENST00000555055.6

TSL:1MANE Select

HGVSc / HGVSpc.-316A>T

Exon rankExon 2 of 10

5_prime_UTR

Prot: ENSP00000452598.1UniProt: O43542

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:152112	Cov:34
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:0
GnomAD4 genome Warning	AF: 0.00000657	AC:1	Hom:0	AN:152232	Cov:34

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.4
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.85
GPN-Star LLR	N/A	-0.063
GPN-Star score	N/A	0.063
PhyloP100	Benign	-0.43
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
Pangolin (max)	Benign	0.060
SpliceAI score (max)	Benign	0.17	Details are displayed if max score is > 0.2

Showing 3 of 3 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: rs1799794;

hg19: chr14-104179267;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar